Bicyclic heteroaryl derivatives and preparation and uses thereof

ABSTRACT

The present invention relates compounds of Formula (A), as well as their preparation and uses, and further relates pharmaceutical compositions comprising these compounds and their uses as modulators of dysfunctional glutamate transmission. The present invention also relates to uses of the compounds or pharmaceutical compositions in treating or preventing certain neurological and psychiatric disorders and diseases as well as cancer in humans.

This application is a continuation of U.S. application Ser. No.17/083,877 filed on Oct. 29, 2020, now allowed, which is a continuationof U.S. application Ser. No. 16/791,243, filed on Feb. 14, 2020, whichissued as U.S. Pat. No. 10,882,832, which is divisional of U.S.application Ser. No. 16/587,571, filed on Sep. 30, 2019, which issued asU.S. Pat. No. 10,640,476, which claims the benefit under 35 U.S.C. §111(a) of PCT International Application No. PCT/CN2017/078873, filed onMar. 30, 2017, which is incorporated by reference in its entirety.

FIELD

The present invention relates to the field of medicinal technology, inparticular, to certain compounds, their preparation and uses, as well aspharmaceutical compositions comprising such compounds. As exemplified,the present invention relates to certain bicyclic heteroarylderivatives, their preparation, and the corresponding pharmaceuticalcompositions. The compounds and/or pharmaceutical compositions of thepresent invention can be potentially used in the manufacture of amedicament for preventing, treating, ameliorating certain disorder or adisease in a patient, which includes, inter alia, a neurological orpsychiatric disorder or disease, as well as a cancer. It is believedthat the compounds and/or pharmaceutical compositions of the presentinvention exert their therapeutic benefits by, among other things,acting to modulate (e.g., block) dysfunctional glutamate transmission.

BACKGROUND

Based on clinical findings and evidence from their relevant preclinicalmodels, dysfunctional glutamate transmission has important roles in avariety of disease pathologies (e.g., for a compendium). In theprogression of these diseases, the underlying mechanisms for glutamate'srelease and/or uptake significantly involve its intercellulartransmission caused by abnormal intercellular ion flows throughrespective cellular membrane's ion channels. As indicated below, themodulation (e.g., blockade) of these channels by published drugs (eitherdirectly, or via inducing a cascade of intervening pathways) canattenuate such disease progression.

Many neurological and psychiatric diseases involve dysfunctionalglutamate transmission caused by abnormal Na and/or Ca activated K (alsoknown as KCa2, SK) ion channels—(e.g., A. Doble, The Role ofExcitotoxicity in Neurodegenerative Disease: Implications for Therapy,Pharmacol. Ther. Vol. 81 (3), pp. 163-221 and J. Lam, et. al. TheTherapeutic Potential of Small-Conductance KCa2 Channels inNeurodegenerative and Psychiatric Diseases, Expert Opin Ther TargetsVol. 17(10), pp. 1203-1220). Such neurodegenerative diseases includeamyotrophic lateral sclerosis (ALS), chronic pain such as neuropathy,multiple sclerosis (MS), ataxia, Parkinson's disease, Huntington'sdisease, Tourette syndrome, epilepsy, dystonia, Fragile X syndrome anddisorders resulting from traumatic brain/spinal cord injuries or fromcerebral ischemia. Psychiatric diseases include depression, anxiety,bipolar disorder, schizophrenia, obsessive compulsive disorder, autism,glaucoma induced optical neuropathy and alcohol/drug addiction.Cognitive dysfunctions include but not limited to dementia (vascular andAlzheimer's disease) and attention deficit/hyperactive disorder (ADHD).Unfortunately when the above mentioned diseases/disorders areprogressive, they resist currently approved drug therapies at latestages or become resistant after starting drug therapies at earlierstages. For example in major depression, significant patient populations(10-55% depending on the database accessed) are/become ‘treatmentresistant’. In epilepsy, a significant minority (20-30%) of patientsare/become resistant to currently approved drugs. Epilepsy, a complexneurological disorder estimated to affect over 50 million peopleworldwide, is characterized by recurrent spontaneous seizures due toneuronal hyperexcitability and hypersynchronous neural firing. Despitethe availability of more than 20 antiepileptic drugs (AEDs), 30% ofpatients with epilepsy continue to experience seizures or suffer fromundesirable drug side effects such as drowsiness, behavior changes,liver damage or teratogenicity.

In addition, the glutamate uptake involving tumor cell's Na-receptorchannels is believed to potentiate cancer metastasis (e.g., M. B. A.Djamgoz, Persistent Current Blockers of Voltage-Gated Sodium Channels: AClinical Opportunity for Controlling Metastatic Disease, Recent PatAnticancer Drug Discov. Vol. 8(1), pp. 66-84 and T. Koltai,Voltage-gated sodium channel as a target for metastatic risk reductionwith re-purposed drugs, F1000 Research Vol. 4, p. 297). In a Phase 2clinical trial of patients having metastatic melanoma and then treatedwith Riluzole (for which the current marketing approval is only to treatALS. In the clinical trial, metastasis was initially stabilized in 42%despite no overall improvement of RECIST grade. To further improveRiluzole's efficacy to treat metastatic melanoma, a combination therapywith other anticancer drugs was proposed.

Therefore, novel drugs are urgently needed to treat these ‘resistant’patients whether as monotherapy or integrated into combination regimens(e.g., some combinations of existing drugs to treat epilepsy: N.Matsumura, Isobolographic analysis of the mechanisms of action ofanticonvulsants from a combination effect, European Journal ofPharmacology, Vol. 741, pp. 237-246).

The compounds and pharmaceutical formulations disclosed in the presentapplication are believed to be effective in providing the neededsolution of achieving modulation of dysfunctional glutamate transmissionfor the aforementioned therapeutic indications.

SUMMARY

The following is only an overview of some aspects of the presentinvention, but is not limited thereto. All references of thisspecification are incorporated herein by reference in their entirety.When the disclosure of this specification is different with citations,the disclosure of this specification shall prevail. The presentinvention provides compounds and pharmaceutical compositions whichmodulates dysfunctional glutamate transmission via sodium channels andKCa2 channels, which include certain bicyclic heteroaryl derivatives,their preparation, and the corresponding pharmaceutical compositions.The compounds and/or pharmaceutical compositions of the presentinvention can be potentially used in the manufacture of a medicament forpreventing, treating, ameliorating certain disorder or a disease in apatient, which includes, inter alia, a neurological or psychiatricdisorder or disease, as well as a cancer.

One aspect of the present invention is the provision of a compound ofFormula (A):

wherein,

-   -   X is NH, O, S or Se;    -   W₁ or W₂ is CH or N, provided that W₁ and W₂ are not both N;    -   R₁ and R₂ are the same, or they are different, and are        independently selected from the group consisting of:        -   hydrogen and        -   GR^(a), wherein G is absent, —C(O)— or —C(O)O— and R^(a) is            a saturated straight or branched alkyl of from one to four            carbon atoms, or a saturated cycloalkyl of from three to six            carbon atoms, provided that R₁ and R₂ are not both GR^(a),            wherein G is not absent;    -   Y_(q) is selected from the group consisting of hydrogen,        deuterium, SF₅, CF₃, OCF₃, SCF₃, S(O)CF₃, S(O)₂CF₃, CN, SCN,        S(O)CH₃, S(O)₂CH₃, NO₂, and wherein q is 1 or 2; provided that        when q is 2, Y₁ and Y₂ can be the same, or different, and they        are not both hydrogen, or both deuterium, or one each of        hydrogen and deuterium;    -   or a pharmaceutically acceptable salt thereof, and        -   with the proviso that when W₁ and W₂ are CH, the compound of            Formula (A) is not one of the following compounds:

wherein R₁ or R₂ are as above defined; and

with the proviso that when W₁ or W₂ is N, the compound of Formula (A) isnot one of the following compounds:

wherein R₁ or R₂ are as above defined.

In a further aspect, the invention relates to pharmaceuticalcompositions each comprising an effective amount of at least onecompound of Formula (A) or a pharmaceutically acceptable salt of acompound of Formula (A). Pharmaceutical compositions according to theinvention may further comprise at least one pharmaceutically acceptableexcipient, carrier, adjuvant, solvent, support or a combination thereof.

In another aspect, the invention is directed to a method of treating asubject suffering from, inter alia, a neurological or psychiatricdisease or disorder or medical condition of a cancer, that is mediatedby dysfunctional glutamate transmission, comprising administering to thesubject in need of such treatment an effective amount of at least onecompound of Formula (A) or a pharmaceutically acceptable salt of acompound of Formula (A), or comprising administering to the subject inneed of such treatment an effective amount of a pharmaceuticalcomposition comprising an effective amount of at least one compound ofFormula (A) or a pharmaceutically acceptable salt of a compound ofFormula (A).

An aspect of the present invention concerns the use of compound ofFormula (A) for the preparation of a medicament used in the treatment,prevention, inhibition or elimination of a neurological and psychiatricdisorder or disease, which medicament further comprises therapeuticallyeffective amounts of one or more, optional, adjunctive activeingredients, which adjunctive active ingredient comprises anantipsychotic, an atypical antipsychotic, an antiepileptic, ananti-Parkinson's disease drug, an anti-amyotrophic lateral sclerosisdrug, anti-pain drug, anti-multiple sclerosis drug, spinal cord injuryor a combination thereof, selected from the group consisting ofriluzole, amitriptyline, desipramine, mirtazapine, bupropion,reboxetine, fluoxetine, trazodone, sertraline, duloxetine, fluvoxamine,milnacipran, levomilnacipran, desvenlafaxine, vilazodone, venlafaxine,dapoxetine, nefazodone, femoxetine, clomipramine, citalopram,escitalopram, paroxetine, lithium carbonate, buspirone, olanzapine,quetiapine, risperidone, ziprasidone, aripiprazole, perospirone,clozapine, modafinil, mecamylamine, cabergoline, adamantane, imipramine,pramipexole, thyroxine, dextromethorphan, quinidine, naltrexone,samidorphan, buprenorphine, melatonin, alprazolam, pipamperone,vestipitant, perphenazine, midazolam, triazolam, estazolam, diazepam,flurazepam, nitrazepam, clonazepam, temazepam, flunitrazepam, oxazepam,zolpidem, zaleplon, zopiclone, eszopiclone, indiplon, tiagabine,gaboxadol, clomipramine, doxepin, chloral hydrate, haloperidol,chlorpromazine, carbamazepine, promethazine, lorazepam, hydroxyzine,aspirin, diphenhydramine, chlorpheniramine, lendormin, ramelteon,tasimelteon, agomelatine, mianserin, femoxetine, nabilone, doxepin,gabapentin, chlordiazepoxide, suvorexant, Xuezang Guben or a combinationthereof.

An aspect of the present invention concerns the use of compound ofFormula (A) for the preparation of a medicament used in the treatment,prevention, inhibition or elimination of a cancer, which medicamentfurther comprises therapeutically effective amounts of one or more,optional, adjunctive active ingredients, which adjunctive activeingredient comprises a chemotherapeutic agent, selected from the groupconsisting of: cytotoxic agent, cisplatin, doxorubicin, taxotere, taxol,etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, theepothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide,cyclophosphamide, SCH 66336, tipifarnib (Zarnestra®), RI 15777,L778,123, BMS 214662, Iressa®, Tarceva®, C225, GLEEVEC®, Intron®,Peg-Intron®, aromatase combinations, ara-C, adriamycin, ercept,gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan,Chlorambucil, Pipobroman, Triethylenemelamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin,oxaliplatin (ELOXATIN®), Pentostatine, Vinblastine, Vincristine,Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Epirubicin,Idarubicin, Mithramycin™, Deoxycoformycin, Mitomycin-C, L-Asparaginase,Teniposide 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone,Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone,Megestrol acetate, Methylprednisolone, Methyltestosterone, Prednisolone,Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide,Toremifene, goserelin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin,Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa,Altretamine, Melphalan, Trastuzumab, Fulvestrant, Exemestane,Ifosfomide, Rituximab, Campath, leucovorin, and dexamethasone,bicalutamide, carboplatin, chlorambucil, letrozole, megestrol, andvalrubicin, or a combination thereof.

Another aspect of the present invention concerns the use of a compoundof Formula (A) for the preparation of a medicament used in thetreatment, prevention, inhibition or elimination of a disorder ordisease or medical condition in a patient by modulating glutamatetransmission in said patient, wherein said disorder or disease ormedical condition is selected from the group consisting of: glioma,breast cancer, melanoma; amyotrophic lateral sclerosis (ALS), chronicneuropathy pain, multiple sclerosis, ataxia, Parkinson's, Huntington's,Tourette syndrome, epilepsy, dystonia, Fragile X syndrome, disordersresulting from traumatic brain/spinal cord injuries, disorders resultingfrom cerebral ischemia; depression, anxiety, bipolar disorder,schizophrenia, obsessive compulsive disorder, autism, alcohol/drugaddiction; vascular and Alzheimer's dementia, glaucoma induced opticalneuropathy and attention deficit/hyperactive disorder (ADHD).

In yet another aspect of the present invention, the compounds of Formula(A) and pharmaceutically acceptable salts thereof are useful asmodulators of glutamate transmission. Thus, the invention is directed toa method for modulating glutamate transmission in a subject, comprisingexposing the subject to an effective amount of at least one compound ofFormula (A) or a pharmaceutically acceptable salt of a compound ofFormula (A).

In yet another aspect, the present invention is directed to methods ofmaking compounds of Formula (A) and pharmaceutically acceptable saltsthereof.

In certain embodiments of the compounds, pharmaceutical compositions,and methods of the invention, the compound of Formula (A) is a compoundselected from those species described or exemplified in the detaileddescription below, or is a pharmaceutically acceptable salt of such acompound.

Another preferred embodiment, the present invention is directed tomethods of preparing pharmaceutical compositions each comprising aneffective amount of at least one compound of Formula (A) or apharmaceutically acceptable salt of a compound of Formula (A).Pharmaceutical compositions according to the invention may furthercomprise at least one pharmaceutically acceptable excipient, carrier,adjuvant, solvent, support or a combination thereof.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described herein (oras known to those skilled in the art) and the other pharmaceuticallyactive agents or treatments within its dosage range. For example, theCDC2 inhibitor olomucine has been found to act synergistically withknown cytotoxic agents in inducing apoptosis (J. Cell Sci., (1995) 108,2897). The compounds of the invention may also be administeredsequentially with known anticancer or cytotoxic agents when acombination formulation is inappropriate. In any combination treatment,the invention is not limited in the sequence of administration;compounds of Formula (A) may be administered either prior to or afteradministration of the known anticancer or cytotoxic agent. For example,the cytotoxic activity of the cyclin-dependent kinase inhibitorflavopiridol is affected by the sequence of administration withanticancer agents (Cancer Research, (1997) 57, 3375). Such techniquesare within the skills of persons skilled in the art as well as attendingphysicians.

Any of the aforementioned methods may be augmented by administration offluids (such as water), loop diuretics, one or more of achemotherapeutic or antineoplastic agent, such as leucovorin andfluorouracil, and an adjunctive chemotherapeutic agent (such asfilgrastim and erythropoietin), or any combination of the foregoing.

Yet another embodiment is a method for administering a compound of theinstant invention to a subject (e.g., a human) in need thereof byadministering to the subject the pharmaceutical formulation of thepresent invention.

Yet another embodiment is a method of preparing a pharmaceuticalformulation of the present invention by mixing at least onepharmaceutically acceptable compound of the present invention, and,optionally, one or more pharmaceutically acceptable additives orexcipients.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, beads, cachets andsuppositories. The powders and tablets may be comprised of from about 5to about 95 percent active ingredient. Suitable solid carriers are knownin the art, e.g., magnesium carbonate, magnesium stearate, talc, sugaror lactose. Tablets, powders, cachets and capsules can be used as soliddosage forms suitable for oral administration. Examples ofpharmaceutically acceptable carriers and methods of manufacture forvarious compositions may be found in A. Gennaro (ed.), Remington'sPharmaceutical Sciences, 18^(th) Edition, (1990), Mack Publishing Co.,Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g., nitrogen.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

The compounds of this invention may also be delivered subcutaneously.

Preferably the compound is administered orally or intravenously.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 1 mg to about 1000 mg, preferably fromabout 1 mg to about 500 mg, more preferably from about 1 mg to about 250mg, still more preferably from about 1 mg to about 50 mg, according tothe particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required. Theamount and frequency of administration of the compounds of the inventionand/or the pharmaceutically acceptable salts thereof will be regulatedaccording to the judgment of the attending clinician considering suchfactors as age, condition and size of the patient as well as severity ofthe symptoms being treated. A typical recommended daily dosage regimenfor oral administration can range from about 1 mg/day to about 200mg/day, preferably 10 mg/day to 100 mg/day, in one to two divided doses.

Any embodiment disclosed herein can be combined with other embodimentsas long as they are not contradictory to one another, even though theembodiments are described under different aspects of the invention. Inaddition, any technical feature in one embodiment can be applied to thecorresponding technical feature in other embodiments as long as they arenot contradictory to one another, even though the embodiments aredescribed under different aspects of the invention.

The foregoing merely summarizes certain aspects disclosed herein and isnot intended to be limiting in nature. These aspects and other aspectsand additional embodiments, features, and advantages of the inventionwill be apparent from the following detailed description and throughpractice of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other aspects and advantages of embodiments of the presentdisclosure will become apparent and more readily appreciated from thefollowing descriptions made with reference the accompanying schemes anddrawings, in which:

FIGS. 1A and 1B show the inhibitory effect of Compound I on hNav1.2/1.7channel.

FIG. 2 shows the anti-allodynic effects of the Compound I in SNL rats.

FIG. 3 shows the pharmacokinetic parameters of Compound I in rats.

DETAILED DESCRIPTION

For the sake of brevity, the disclosures of the publications cited inthis specification, including patents and patent applications, areherein incorporated by reference in their entirety.

Most chemical names were generated using IUPAC nomenclature herein. Somechemical names were generated using different nomenclatures oralternative or commercial names known in the art. In the case ofconflict between names and structures, the structures prevail.

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulas. The invention is intended to cover allalternatives, modifications and equivalents which may be included withinthe scope of the present invention as defined by the claims. One skilledin the art will recognize many methods and materials similar orequivalent to those described herein, which could be used in thepractice of the present invention. The present invention is in no waylimited to the methods and materials described herein. In the event thatone or more of the incorporated literature, patents, and similarmaterials differs from or contradicts this application, including butnot limited to defined terms, term usage, described techniques, or thelike, this application controls.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable sub-combination.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as are commonly understood by one skilled in theart to which this invention belongs. All patents and publicationsreferred to herein are incorporated by reference in their entirety.

As used herein, the following definitions shall apply unless otherwiseindicated. For purposes of this invention, the chemical elements areidentified in accordance with the Periodic Table of the Elements, CASversion, and the Handbook of Chemistry and Physics, 75th Ed. 1994.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry” by Michael B.Smith and Jerry March, John Wiley & Sons, New York: 2007, the entirecontents of which are hereby incorporated by reference.

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings. If a definition is missing, the conventional definition asknown to one skilled in the art controls. If a definition providedherein conflicts or is different from a definition provided in any citedpublication, the definition provided herein controls.

As used herein, the terms “including”, “containing”, and “comprising”are used in their open, non-limiting sense.

As used herein, the singular forms “a”, “an”, and “the” include pluralreferents unless the context clearly dictates otherwise.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently.

As used herein, “alkyl” refers to a saturated, straight- orbranched-chain hydrocarbon group having from 1 to 12 carbon atoms.Representative alkyl groups include, but are not limited to, methyl,ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl,2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl,neopentyl, n-hexyl, and the like, and longer alkyl groups, such asheptyl, octyl, and the like. As used herein, “lower alkyl” means analkyl having from 1 to 6 carbon atoms.

The term “alkylamino” as used herein denotes an amino group as definedherein wherein one hydrogen atom of the amino group is replaced by analkyl group as defined herein. Aminoalkyl groups can be defined by thefollowing general formula —NH-alkyl. This general formula includesgroups of the following general formulae: —NH—C₁-C₁₀ alkyl and —NH—C₁-C₆alkyl. Examples of aminoalkyl groups include, but are not limited toaminomethyl, aminoethyl, aminopropyl, aminobutyl.

The term “dialkylamino” as used herein denotes an amino group as definedherein wherein two hydrogen atoms of the amino group are replaced byalkyl groups as defined herein. Diaminoalkyl groups can be defined bythe following general formula —N(alkyl)₂, wherein the alkyl groups canbe the same or can be different and can be selected from alkyls asdefined herein, for example C₁-C₁₀ alkyl or C₁-C₆ alkyl.

The term “alkoxy” as used herein includes —O-(alkyl), wherein alkyl isdefined above.

As used herein, “alkoxyalkyl” means -(alkylenyl)-O-(alkyl), wherein each“alkyl” is independently an alkyl group defined above.

The term “amino” as used herein refers to an —NH₂ group.

“Aryl” means a mono-, bi-, or tricyclic aromatic group, wherein allrings of the group are aromatic. For bi- or tricyclic systems, theindividual aromatic rings are fused to one another. Exemplary arylgroups include, but are not limited to, phenyl, naphthalene, andanthracene.

“Aryloxy” as used herein refers to an —O-(aryl) group, wherein aryl isdefined as above.

“Arylalkyl” as used herein refers to an -(alkylenyl)-(aryl) group,wherein alkylenyl and aryl are as defined above. Non-limiting examplesof arylalkyls comprise a lower alkyl group. Non-limiting examples ofsuitable arylalkyl groups include benzyl, 2-phenethyl, andnaphthalenylmethyl.

“Arylalkoxy” as used herein refers to an —O-(alkylenyl)-aryl groupwherein alkylenyl and aryl are as defined above.

The term “cyano” as used herein means a substituent having a carbon atomjoined to a nitrogen atom by a triple bond.

The term “cyanoalkyl” denotes an alkyl group as defined above wherein ahydrogen atom of the alkyl group is replaced by a cyano (—CN) group. Thealkyl portion of the cyanoalkyl group provides the connection point tothe remainder of the molecule.

The term “deuterium” as used herein means a stable isotope of hydrogenhaving one proton and one neutron.

The term “halogen” as used herein refers to fluorine, chlorine, bromine,or iodine. The term “halo” represents chloro, fluoro, bromo, or iodo.

The term “haloalkyl” denotes an alkyl group as defined above wherein oneor more, for example one, two, or three of the hydrogen atoms of thealkyl group are replaced by a halogen atom, for example fluoro, bromo,or chloro, in particular fluoro. Examples of haloalkyl include, but arenot limited to, monofluoro-, difluoro-, or trifluoro-methyl, -ethyl or-propyl, for example, 3,3,3-trifluoropropyl, 2-fluoroethyl,2,2,2-trifluoroethyl, fluoromethyl, difluoromethyl, or trifluoromethyl,or bromoethyl or chloroethyl. Similarly, the term “fluoroalkyl” refersto an alkyl group as defined above substituted with one or more, forexample one, two, or three fluorine atoms.

The term “haloalkoxy” as used herein refers to an —O-(haloalkyl) groupwherein haloalkyl is defined as above. Exemplary haloalkoxy groups arebromoethoxy, chloroethoxy, trifluoromethoxy and 2,2,2-trifluoroethoxy.

The term “hydroxy” means an —OH group.

The term “hydroxyalkyl” denotes an alkyl group that is substituted by atleast one hydroxy group, for example, one, two or three hydroxygroup(s). The alkyl portion of the hydroxyalkyl group provides theconnection point to the remainder of a molecule. Examples ofhydroxyalkyl groups include, but are not limited to, hydroxymethyl,hydroxyethyl, 1-hydroxypropyl, 2-hydroxyisopropyl, 1,4-dihydroxybutyl,and the like.

The term “oxo” means an ═O group and may be attached to a carbon atom ora sulfur atom. The term “N-oxide” refers to the oxidized form of anitrogen atom.

As used herein, the term “cycloalkyl” refers to a saturated or partiallysaturated, monocyclic, fused polycyclic, bridged polycyclic, or spiropolycyclic carbocycle having from 3 to 12 ring carbon atoms. Anon-limiting category of cycloalkyl groups are saturated or partiallysaturated, monocyclic carbocycles having from 3 to 6 carbon atoms.Illustrative examples of cycloalkyl groups include, but are not limitedto, the following moieties:

The term “cycloalkoxy” refers to a —O-(cycloalkyl) group.

As used herein, the term “heteroaryl” refers to a monocyclic, or fusedpolycyclic, aromatic heterocycle having from three to 15 ring atoms thatare selected from carbon, oxygen, nitrogen, selenium and sulfur.Suitable heteroaryl groups do not include ring systems that must becharged to be aromatic, such as pyrylium. Some suitable 5-memberedheteroaryl rings (as a monocyclic heteroaryl or as part of a polycyclicheteroaryl) have one oxygen, sulfur, or nitrogen atom, or one nitrogenplus one oxygen or sulfur, or 2, 3, or 4 nitrogen atoms. Some suitable6-membered heteroaryl rings (as a monocyclic heteroaryl or as part of apolycyclic heteroaryl) have 1, 2, or 3 nitrogen atoms. Examples ofheteroaryl groups include, but are not limited to, pyridinyl,imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl,pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl,benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl,quinoxalinyl, naphthyridinyl, and furopyridinyl.

The term “bicyclic heteroaryl” refers to a heteroaryl as defined above,having two constituent aromatic rings, wherein the two rings are fusedto one another and at least one of the rings is a heteroaryl as definedabove. Bicyclic heteroaryls include bicyclic heteroaryl groupscomprising 1, 2, 3, or 4 heteroatom ring members and are unsubstitutedor substituted with one or more substituents selected from the groupconsisting of amino and halo; and wherein one or more N ring members ofsaid heteroaryl is optionally an N-oxide. Bicyclic heteroaryls alsoinclude 8-, 9-, or 10-membered bicyclic heteroaryl groups. Bicyclicheteroaryls also include 8-, 9-, or 10-membered bicyclic heteroarylgroups that have 1, 2, 3 or 4 heteroatom ring members and that areunsubstituted or substituted with one or more substituents selected fromthe group consisting of amino and halo; and wherein one or more N ringmembers of said heteroaryl is optionally an N-oxide. Illustrativeexamples of bicyclic heteroaryls with respect to the present inventioninclude, but are not limited to:

Those skilled in the art will recognize that the species of heteroaryl,and cycloalkyl groups listed or illustrated above are not exhaustive,and that additional species within the scope of these defined terms mayalso be selected.

As described herein, compounds disclosed herein may optionally besubstituted with one or more substituents, or as exemplified byparticular classes, subclasses, and species of the invention.

As used herein, the term “substituted” means that the specified group ormoiety bears one or more suitable substituents. As used herein, the term“unsubstituted” means that the specified group bears no substituents. Asused herein, the term “optionally substituted” means that the specifiedgroup is unsubstituted or substituted by the specified number ofsubstituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system.

As used herein, the expression “one or more substituents” denotes one tomaximum possible number of substitution(s) that can occur at anyvalency-allowed position on the system. In a certain embodiment, one ormore substituent means 1, 2, 3, 4, or 5 substituents. In anotherembodiment, one or more substituent means 1, 2, or 3 substituents.

Any atom that is represented herein with an unsatisfied valence isassumed to have the sufficient number of hydrogen atoms to satisfy theatom's valence.

When any variable (e.g., alkyl, alkylenyl, heteroaryl, R₁, R₂, or R_(a))appears in more than one place in any formula or description providedherein, the definition of that variable on each occurrence isindependent of its definition at every other occurrence.

Numerical ranges, as used herein, are intended to include sequentialwhole numbers. For example, a range expressed as “from 0 to 4” or “0-4”includes 0, 1, 2, 3 and 4, while a range expressed as “10-20%” includes10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% and 20%. Similarly,numerical ranges are also intended to include sequential fractionalintegers. For example, a range expressed as “1-2%” would include 1.0%,1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9% and 2.0%.

When a multifunctional moiety is shown, the point of attachment to thecore is indicated by a line or hyphen. For example, aryloxy—refers to amoiety in which an oxygen atom is the point of attachment to the coremolecule while aryl is attached to the oxygen atom.

As used herein, the term “subject” encompasses mammals and non-mammals.Examples of mammals include, but are not limited to, any member of theMammalian class: humans; non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;and laboratory animals including rodents, such as rats, mice and guineapigs, and the like. Examples of non-mammals include, but are not limitedto, birds, fish and the like. In one embodiment of the presentinvention, the mammal is a human.

“Patient” includes both human and animals.

The term “inhibitor” refers to a molecule such as a compound, a drug, anenzyme activator, or a hormone that blocks or otherwise interferes witha particular biologic activity.

The term “modulator” refers to a molecule, such as a compound of thepresent invention, that increases or decreases, or otherwise affects theactivity of a given protein, receptor and/or ion channels.

The terms “effective amount” or “therapeutically effective amount” referto a sufficient amount of the agent to provide the desired biologicalresult. That result can be reduction and/or alleviation of the signs,symptoms, or causes of a disease or medical condition, or any otherdesired alteration of a biological system. For example, an “effectiveamount” for therapeutic use is the amount of a compound, or of acomposition comprising the compound, that is required to provide aclinically relevant change in a disease state, symptom, or medicalcondition. An appropriate “effective” amount in any individual case maybe determined by one of ordinary skill in the art using routineexperimentation. Thus, the expression “effective amount” generallyrefers to the quantity for which the active substance has atherapeutically desired effect.

As used herein, the terms “treat” or “treatment” encompass both“preventative” and “curative” treatment. “Preventative” treatment ismeant to indicate a postponement of development of a disease, a symptomof a disease, or medical condition, suppressing symptoms that mayappear, or reducing the risk of developing or recurrence of a disease orsymptom. “Curative” treatment includes reducing the severity of orsuppressing the worsening of an existing disease, symptom, or condition.Thus, treatment includes ameliorating or preventing the worsening ofexisting disease symptoms, preventing additional symptoms fromoccurring, ameliorating or preventing the underlying metabolic causes ofsymptoms, inhibiting the disorder or disease, e.g., arresting thedevelopment of the disorder or disease, relieving the disorder ordisease, causing regression of the disorder or disease, relieving acondition caused by the disease or disorder, or stopping the symptoms ofthe disease or disorder.

As used herein, the terms “administration of” and “administering a”compound should be understood to mean providing a compound of theinvention, pharmaceutical composition comprising a compound or a prodrugof a compound of the invention to an individual in need thereof. It isrecognized that one skilled in the non-limiting art can treat a patientpresently afflicted with neurological and psychiatric disorders or byprophylactically treat a patient afflicted with the disorders with aneffective amount of the compound of the present invention.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationsof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s) and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from a combination, complexation or aggregation of anytwo or more of the ingredients, or from the other types of reactions orinteractions such as to cause the dissociation of one or more of theingredients. Accordingly, the pharmaceutical compositions of the presentinvention encompass any composition made by mixing a compound of thepresent invention and a pharmaceutically acceptable carrier.

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. For example, compounds of any formula given hereinmay have asymmetric or chiral centers and therefore exist in differentstereoisomeric forms. All stereoisomers, including optical isomers,enantiomers, and diastereomers, of the compounds of the general formula,and mixtures thereof, are considered to fall within the scope of theformula. Furthermore, certain structures may exist as geometric isomers(i.e., cis and trans isomers), as tautomers, or as atropisomers. Allsuch isomeric forms, and mixtures thereof, are contemplated herein aspart of the present invention. Thus, any formula given herein isintended to represent a racemate, one or more enantiomeric forms, one ormore diastereomeric forms, one or more tautomeric or atropisomericforms, and mixtures thereof.

“Stereoisomer” refers to compounds which have identical chemicalconstitution, but differ with regard to the arrangement of the atoms orgroups in space. Stereoisomers include enantiomer, diastereomers,conformer (rotamer), geometric (cis/trans) isomer, atropisomer etc.

“Chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

“Enantiomers” refers to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g., melting points,boiling points, spectral properties or biological activities. A mixtureof diastereomers may be separated under high resolution analyticalprocedures such as electrophoresis and chromatography such as HPLC.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994.

Many organic compounds exist in optically active forms, i.e., they havethe ability to rotate the plane of polarized light. In describing anoptically active compound, the prefixes D and L, or R and S, are used todenote the absolute configuration of the molecule about its chiralcenter(s). The prefixes d and l or (+) and (−) are employed to designatethe sign of rotation of plane-polarized light by the compound, with (−)or l meaning that the compound is levorotatory. A compound prefixed with(+) or d is dextrorotatory. A specific stereoisomer may be referred toas an enantiomer, and a mixture of such stereoisomers is called anenantiomeric mixture. A 50:50 mixture of enantiomers is referred to as aracemic mixture or a racemate, which may occur where there has been nostereoselection or stereospecificity in a chemical reaction or process.

Any asymmetric atom (e.g., carbon or the like) of the compound(s)disclosed herein can be in racemic or enantiomerically enriched, forexample the (R)-, (S)- or (R,S)-configuration. In certain embodiments,each asymmetric atom has at least 50% enantiomeric excess, at least 60%enantiomeric excess, at least 70% enantiomeric excess, at least 80%enantiomeric excess, at least 90% enantiomeric excess, at least 95%enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or(S)-configuration.

Depending on the choice of the starting materials and procedures, thecompounds can be present in the form of one of the possiblestereoisomers or as mixtures thereof, such as racemates anddiastereoisomer mixtures, depending on the number of asymmetric carbonatoms. Optically active (R)- and (S)-isomers may be prepared usingchiral synthons or chiral reagents, or resolved using conventionaltechniques. If the compound contains a double bond, the substituent maybe E or Z configuration. If the compound contains a disubstitutedcycloalkyl, a cycloalkyl substituent may have a cis- ortrans-configuration relative to another substituent of the samecycloalkyl frame.

Any resulting mixtures of stereoisomers can be separated on the basis ofthe physicochemical differences of the constituents, into the pure orsubstantially pure geometric isomers, enantiomers, diastereomers, forexample, by chromatography and/or fractional crystallization. Anyresulting racemates of final products or intermediates can be resolvedinto the optical antipodes by methods known to those skilled in the art,e.g., by separation of the diastereomeric salts thereof. Racemicproducts can also be resolved by chiral chromatography, e.g., highperformance liquid chromatography (HPLC) using a chiral adsorbent.Preferred enantiomers can also be prepared by asymmetric syntheses. See,for example, Jacques, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis(2nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, U K, 2012);Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, N Y,1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutionsp. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind.1972); Chiral Separation Techniques: A Practical Approach (Subramanian,G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

Diastereomeric mixtures may be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers may beseparated by converting the enantiomenc mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride, orformation of a mixture of diastereomeric salts), separating thediastereomers and converting (e.g., hydrolyzing or de-salting) theindividual diastereomers to the corresponding pure enantiomers.Enantiomers may also be separated by use of chiral HPLC column.

The compounds of the invention can form pharmaceutically acceptablesalts, which are also within the scope of this invention. A“pharmaceutically acceptable salt” refers to a salt of a free acid orbase of a compound of Formula I that is non-toxic, is physiologicallytolerable, is compatible with the pharmaceutical composition in which itis formulated, and is otherwise suitable for formulation and/oradministration to a subject. Reference to a compound herein isunderstood to include reference to a pharmaceutically acceptable salt ofsaid compound unless otherwise indicated.

Compound salts include acidic salts formed with inorganic and/or organicacids, as well as basic salts formed with inorganic and/or organicbases. In addition, where a given compound contains both a basic moiety,such as, but not limited to, a pyridine or imidazole, and an acidicmoiety, such as, but not limited to, a carboxylic acid, one of skill inthe art will recognize that the compound may exist as a zwitterion(“inner salt”); such salts are included within the term “salt” as usedherein. Salts of the compounds of the invention may be prepared, forexample, by reacting a compound with an amount of a suitable acid orbase, such as an equivalent amount, in a medium such as one in which thesalt precipitates or in an aqueous medium followed by lyophilization.

Exemplary salts include, but are not limited, to sulfate, citrate,acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate,phosphate, acid phosphate, isonicotinate, lactate, salicylate, acidcitrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,succinate, maleate, gentisinate, fumarate, gluconate, glucuronate,saccharate, formate, benzoate, glutamate, methanesulfonate (“mesylate”),ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate(i.e., 1,1′-methylene-bis(2-hydroxy-3-naphthoate)) salts. Apharmaceutically acceptable salt may involve the inclusion of anothermolecule such as an acetate ion, a succinate ion or other counterion.The counterion may be any organic or inorganic moiety that stabilizesthe charge on the parent compound. Furthermore, a pharmaceuticallyacceptable salt may have more than one charged atom in its structure.Instances where multiple charged atoms are part of the pharmaceuticallyacceptable salt can have multiple counterions. Hence, a pharmaceuticallyacceptable salt can have one or more charged atoms and/or one or morecounter ion.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, tert-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g., decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g., benzyl andphenethyl bromides), and others.

Additionally, acids and bases which are generally considered suitablefor the formation of pharmaceutically useful salts from pharmaceuticalcompounds are discussed, for example, by P. Stahl et al, Camille G.(eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use.(2002) Zurich: Wiley-VCH; S. Berge et al, Journal of PharmaceuticalSciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics(1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry(1996), Academic Press, New York; and in The Orange Book (Food & DrugAdministration, MD, available from FDA). These disclosures areincorporated herein by reference thereto.

Additionally, any compound described herein is intended to refer also toany unsolvated form, or a hydrate, solvate, or polymorph of such acompound, and mixtures thereof, even if such forms are not listedexplicitly. “Solvate” means a physical association of a compound of theinvention with one or more solvent molecules. This physical associationinvolves varying degrees of ionic and covalent bonding, includinghydrogen bonding. In certain instances the solvate will be capable ofisolation, for example when one or more solvent molecules areincorporated in the crystal lattice of a crystalline solid. “Solvate”encompasses both solution-phase and isolatable solvates. Suitablesolvates include those formed with pharmaceutically acceptable solventssuch as water, ethanol, and the like. In some embodiments, the solventis water and the solvates are hydrates.

One or more compounds of the invention may optionally be converted to asolvate. Methods for the preparation of solvates are generally known.Thus, for example, M. Caira et al., J. Pharmaceutical Sci., 93(3),601-611 (2004), describes the preparation of the solvates of theantifungal fluconazole in ethyl acetate as well as from water. Similarpreparations of solvates, hemisolvate, hydrates, and the like aredescribed by E. C. van Tonder et al, AAPS PharmSciTech., 5(1), article12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001). Atypical, non-limiting process involves dissolving the compound of theinvention in a suitable amount of the solvent (organic solvent or wateror a mixture thereof) at a higher than ambient temperature, and coolingthe solution at a rate sufficient to form crystals which are thenisolated by standard methods. Analytical techniques such as, forexample, infrared spectroscopy, show the presence of the solvent (orwater) in the crystals as a solvate (or hydrate).

The present invention also relates to pharmaceutically activemetabolites of compounds of Formula (A), and uses of such metabolites inthe methods of the invention. A “pharmaceutically active metabolite”means a pharmacologically active product of metabolism in the body of acompound of Formula (A) or salt thereof. Active metabolites of acompound may be determined using routine techniques known or availablein the art. See, e.g., Bertolini et al., J Med. Chem. 1997, 40,2011-2016; Shan et al., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe,Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13,255-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); andLarsen, Design and Application of Prodrugs, Drug Design and Development(Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S,¹⁸F, ³⁶Cl, and ¹²⁵I, respectively. Such isotopically labelled compoundsare useful in metabolic studies (for example with ¹⁴C), reaction kineticstudies (with, for example ²H or ³H), detection or imaging techniques[such as positron emission tomography (PET) or single-photon emissioncomputed tomography (SPECT) including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or ¹¹C labeled compound may be particularly suitablefor PET or SPECT studies. Further, substitution with heavier isotopessuch as deuterium (i.e., ²H) may afford certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements. Isotopically labeledcompounds of this invention can generally be prepared by carrying outthe procedures disclosed in the schemes or in the examples andpreparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent.

The use of the terms “salt,” “solvate,” “polymorph,” and the like, withrespect to the compounds described herein is intended to apply equallyto the salt, solvate, and polymorph forms of enantiomers, stereoisomers,rotamers, tautomers, atropisomers, and racemates of the compounds of theinvention.

The present invention relates to particular molecules andpharmaceutically acceptable salts or isomers thereof. The inventionfurther relates to molecules which are useful in modulatingdysfunctional glutamate transmission and pharmaceutically acceptablesalts, solvates, esters, or isomers thereof.

The invention is directed to compounds as described herein andpharmaceutically acceptable salts, solvates, esters, or isomers thereof,and pharmaceutical compositions comprising one or more compounds asdescribed herein and pharmaceutically acceptable salts or isomersthereof. One aspect of this invention is the provision of compounds,compositions, kits, and antidotes for modulating glutamate transmissionin mammals having a compound of the Formula (A):

wherein,

-   -   X is NH, O, S or Se;    -   W₁ or W₂ is CH or N, provided that W₁ and W₂ are not both N;    -   R₁ and R₂ are the same, or they are different, and are        independently selected from the group consisting of:        -   Hydrogen and        -   GR^(a), wherein G is absent, —C(O)— or —C(O)O— and R^(a) is            a saturated straight or branched alkyl of from one to four            carbon atoms, or a saturated cycloalkyl of from three to six            carbon atoms, provided that R₁ and R₂ are not both GR^(a),            wherein G is not absent;        -   Y_(q) is selected from the group consisting of hydrogen,            deuterium, SF₅, CF₃, OCF₃, SCF₃, S(O)CF₃, S(O)₂CF₃, CN, SCN,            S(O)CH₃, S(O)₂CH₃, NO₂, and wherein q is 1 or 2; provided            that when q is 2, Y₁ and Y₂ can be the same, or different,            and they are not both hydrogen, or both deuterium, or one            each of hydrogen and deuterium;    -   or a pharmaceutically acceptable salt thereof, and    -   with the proviso that when W₁ and W₂ are CH, the compound of        Formula (A) is not one of the following compounds:

wherein R₁ or R₂ are as above defined; and

with the proviso that when W₁ or W₂ is N, the compound of Formula (A) isnot one of the following compounds:

wherein R₁ or R₂ are as above defined.

In some embodiments, in which compounds having the general Formula (A),X is NH or O or S or Se. In other embodiments, W₁ or W₂ is N providedthat W₁ and W₂ are not both N. In yet other embodiments, W₁ or W₂ is CH.In other embodiments, the core bicyclic heteroaryl is selected from thegroup consisting of:

In still other embodiments, in which compounds having the generalFormula (A), Y_(q) is selected from the group consisting of hydrogen,deuterium, SF₅, CF₃, OCF₃, SCF₃, S(O)CF₃, S(O)₂CF₃, CN, SCN, S(O)CH₃,S(O)₂CH₃, NO₂, where q is 1 or 2, but provided that when q is 2, Y₁ andY₂ can be the same, or different, and they are not both hydrogen, orboth deuterium, or one each of hydrogen and deuterium.

In some embodiments, in which compounds having the general Formula (A),R₁ and R₂ are the same, or they are different, and are independentlyselected from the group consisting of: hydrogen and GR^(a), wherein G isabsent, —C(O)— or —C(O)O— and R^(a) is a saturated straight or branchedalkyl of from one to four carbon atoms, or a saturated cycloalkyl offrom three to six carbon atoms, provided that R₁ and R₂ are not bothGR^(a), wherein G is not absent.

In some embodiments, in which compounds having the general Formula (A),R₁ or R₂ is GR^(a), wherein G is absent and R^(a) is a straight orbranched alkyl of from one to four carbon atoms, and is selected fromthe group consisting of: —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂,—CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂, and —C(CH₃)₃.

In some embodiments, in which compounds having the general Formula (A),R₁ or R₂ is GR^(a), wherein G is absent and R^(a) is a cycloalkyl offrom three to six carbon atoms, and is selected from the groupconsisting of,

optionally, R^(a) is substituted with C₁-C₄ alkyl.

In some embodiments, in which compounds having the general Formula (A),one of R₁ and R₂ is GR^(a), wherein G is —C(O)— and R^(a) is a saturatedstraight or branched alkyl of from one to four carbon atoms, or asaturated cycloalkyl of from three to six carbon atoms, and is selectedfrom the group consisting of:

optionally, R^(a) is substituted with C₁-C₄ alkyl.

In some embodiments, in which compounds having the general Formula (A),one of R₁ and R₂ is GR^(a), wherein G is —C(O)O— and R^(a) is asaturated straight or branched alkyl having from one to four carbonatoms, or a saturated cyclic alkyl having from three to six carbonatoms, and is selected from the group consisting of:

optionally, R^(a) is substituted with C₁-C₄ alkyl.

In other embodiments, in which compounds having the general Formula (A),one of R₁ and R₂ is GR^(a), wherein R^(a) is selected from the groupconsisting of a saturated straight or branched alkyl of from one to fourcarbon atoms, and a saturated cycloalkyl of from three to six carbonatoms, wherein one or more of said carbon atoms is, optionally, anasymmetric atom.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, W₁ and W₂ are CH, X is N,Y₁ is SF₅, Y₂ is H or D, and R₁ and R₂ are defined as above.

Another embodiment of the invention is the provision of a compound,where the various moieties are independently selected, W₁ and W₂ are CH,X is N, Y₁ and Y₂ are SF₅, and R₁ and R₂ are defined as above.

Another embodiment of the invention is the provision of a compound,where the various moieties are independently selected, W₁ and W₂ are CH,X is O, Y₁ is SF₅, Y₂ is H or D, and R₁ and R₂ are defined as above.

Another embodiment of the invention is the provision of a compound,where the various moieties are independently selected, W₁ and W₂ are CH,X is O, Y₁ and Y₂ are SF₅, and R₁ and R₂ are defined as above.

Another embodiment of the invention is the provision of a compound,where the various moieties are independently selected, W₁ and W₂ are CH,X is S, Y₁ is SF₅, Y₂ is H or D, and R₁ and R₂ are defined as above.

Another embodiment of the invention is the provision of a compound,where the various moieties are independently selected, W₁ and W₂ are CH,X is S, Y₁ and Y₂ are SF₅, and R₁ and R₂ are defined as above.

Another embodiment of the invention is the provision of a compound,where the various moieties are independently selected, W₁ and W₂ are CH,X is Se, Y₁ is SF₅, Y₂ is H or D, and R₁ and R₂ are defined as above.

Another embodiment of the invention is the provision of a compound,where the various moieties are independently selected, W₁ and W₂ are CH,X is Se, Y₁ and Y₂ are SF₅, and R₁ and R₂ are defined as above.

Another embodiment of the invention is the provision of a compound,where the various moieties are independently selected, W₁ and W₂ are CH,X is Se, Y₁ is selected from the group consisting of CF₃, OCF₃, SCF₃,S(O)CF₃, S(O)₂CF₃, CN, SCN, S(O)CH₃, S(O)₂CH₃, and NO₂, Y₂ is H or D,and R₁ and R₂ are defined as above.

Another embodiment of the invention is the provision of a compound,where the various moieties are independently selected, W₁ or W₂ is N, Xis selected from the group consisting of N, O, S and Se, Y₁ is SF₅, Y₂is H or D, and R₁ and R₂ are defined as above.

Another embodiment of the invention is the provision of a compound,where the various moieties are independently selected, W₁ or W₂ is N, Xis selected from the group consisting of N, O, S and Se, Y₁ is CF₃, Y₂is H or D, and R₁ and R₂ are defined as above.

Another embodiment of the invention is the provision of a compound,where the various moieties are independently selected, W₁ or W₂ is N, Xis selected from the group consisting of N, O, S and Se, Y₁ is OCF₃, Y₂is H or D, and R₁ and R₂ are defined as above.

Another embodiment of the invention is the provision of a compound,where the various moieties are independently selected, W₁ or W₂ is N, Xis selected from the group consisting of N, O, S and Se, Y₁ is selectedfrom the group consisting of SCF₃, S(O)CF₃, S(O)₂CF₃, CN, SCN, S(O)CH₃,S(O)₂CH₃, and NO₂, Y₂ is H or D, and R₁ and R₂ are defined as above.

In certain embodiments, the compound of Formula (A) is furtherillustrated by the following compound group consisting of:

and pharmaceutically acceptable salts thereof.

An aspect of the present invention concerns compounds disclosed herein.

An aspect of the present invention concerns compounds which are or canbe modulators of dysfunctional glutamate transmission.

An aspect of the present invention concerns the use of a modulator ofdysfunctional glutamate transmission for the preparation of a medicamentused in the treatment, prevention, inhibition or elimination of tumors.

An aspect of the present invention concerns the use of a modulator ofdysfunctional glutamate transmission for the preparation of a medicamentused in the treatment, prevention, inhibition or elimination of adisorder or disease or medical condition in a patient by modulatingdysfunctional glutamate transmission in said patient, wherein saiddisorder or disease or medical condition is selected from the groupconsisting of: glioma, breast cancer, melanoma; amyotrophic lateralsclerosis (ALS), chronic neuropathy pain, multiple sclerosis, ataxia,Parkinson's, Huntington's, Tourette syndrome, epilepsy, dystonia,Fragile X syndrome, disorders resulting from traumatic brain/spinal cordinjuries, disorders resulting from cerebral ischemia; depression,anxiety, bipolar disorder, schizophrenia, obsessive compulsive disorder,autism, alcohol/drug addiction; vascular and Alzheimer's dementia,glaucoma induced optical neuropathy and attention deficit/hyperactivedisorder (ADHD).

The present invention also describes one or more methods of synthesizingthe compounds of the present invention.

The invention also describes one or more uses of the compounds of thepresent invention.

The invention also describes one or more uses of the compounds of thepresent invention with an adjunctive agent such as use with tumornecrosis factor (TNF), granulocyte colony-stimulating factor (GCSF) orother chemotherapeutic agents.

The present invention also describes one or more methods of preparingvarious pharmaceutical compositions comprising the compounds of thepresent invention.

The invention also describes one or more uses of the variouspharmaceutical compositions of the present invention for the preparationof a medicament used in the treatment, prevention, inhibition orelimination of a disorder or disease or medical condition in a patientby modulating dysfunctional glutamate transmission in said patient.

The present invention provides a pharmaceutical composition comprisingcompounds of the present invention, e.g., example compounds. Accordingto the specific examples of the present invention, the pharmaceuticalcomposition can further comprise pharmaceutically acceptable excipient,carrier, adjuvant, solvent and a combination thereof.

The present invention provides a method of treating, preventing orameliorating a disease or disorder, comprising administrating a safe andeffective amount of a combination of drugs containing compounds of theinvention and one or more therapeutic active agents. Among them, thecombination of drugs comprises one or more additional drugs fortreatment of neurological and psychiatric disorders and diseases ofcentral nervous system.

Other drugs for treatment of neurological and psychiatric disorders anddiseases of central nervous system include, but are not limited to: anantipsychotic, an atypical antipsychotic, an antiepileptic, ananti-Parkinson's disease drug, an anti-amyotrophic lateral sclerosisdrug, anti-pain drug or any combination thereof.

The amount of the compound of the pharmaceutical composition disclosedherein refers to an amount which can be effectively detected to modulatedysfunctional glutamate transmission of biology samples and in apatient. The active ingredient may be administered to subjects in needof such treatment in dosage that will provide optimal pharmaceuticalefficacy, which is not limited to the desired therapeutic effects, onthe route of administration, and on the duration of the treatment. Thedosage will vary from patient to patient depending upon the nature andseverity of disease, the patient's weight, special diet then beingfollowed by a patient, concurrent medication, and other factors whichthose skilled in the art will recognize. The quantity of active compoundin a unit dose of preparation may be varied or adjusted from about 1 mgto about 1000 mg, preferably from about 1 mg to about 500 mg, morepreferably from about 1 mg to about 250 mg, still more preferably fromabout 1 mg to about 50 mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required. Theamount and frequency of administration of the compounds of the inventionand/or the pharmaceutically acceptable salts thereof will be regulatedaccording to the judgment of the attending clinician considering suchfactors as age, condition and size of the patient as well as severity ofthe symptoms being treated. A typical recommended daily dosage regimenfor oral administration can range from about 1 mg/day to about 200mg/day, preferably 10 mg/day to 100 mg/day, which may be administered insingle or multiple doses. In yet another embodiment about 1 mg to 50 mgper patient per day.

It will also be appreciated that certain of the compounds of the presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative or a prodrug thereof. Apharmaceutically acceptable derivative includes pharmaceuticallyacceptable salts, esters, salts of such esters, or any other adduct orderivative which upon administration to a patient in need thereofprovide, directly or indirectly, a compound as otherwise describedherein, or an therapeutically effective metabolite or residue thereof.

The pharmaceutical compositions of the invention may be prepared andpackaged in bulk form wherein a safe and effective amount of a compoundof Formula (A) disclosed herein can be extracted and then given to thepatient, such as with powders or syrups. Generally, dosage levels ofbetween 0.0001 to 10 mg/kg of body weight daily are administered to thepatient to obtain effective modulation of dysfunctional glutamatetransmission. Alternatively, the pharmaceutical compositions of theinvention may be prepared and packaged in unit dosage form wherein eachphysically discrete unit contains a safe and effective amount of acompound of Formula (A) disclosed herein. When prepared in unit dosageform, the pharmaceutical compositions of the invention commonly containfrom about 0.5 mg to 1 g, or 1 mg to 700 mg, or 5 mg to 100 mg, or morepreferably, 25 mg to 60 mg of the compound of the invention.

When the pharmaceutical compositions of the present invention alsocontain one or more other active ingredients, in addition to a compoundof the present invention, the weight ratio of the compound of thepresent invention to the second active ingredient may be varied anddepend upon the effective dose of each ingredient. Thus, for example,when a compound of the present invention is combined with another agent,the weight ratio of the compound of the present invention to the otheragent will generally range from about 1000:1 to about 1:1000, such asabout 200:1 to 1:200. Combinations of a compound of the presentinvention and other active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient in the combination should be used.

“Pharmaceutically acceptable excipient” as used herein means apharmaceutically acceptable material, composition or vehicle involved ingiving form or consistency to the pharmaceutical composition. Eachexcipient must be compatible with the other ingredients of thepharmaceutical composition when commingled, such that interactions whichwould substantially reduce the efficacy of the compound of the inventionwhen administered to a patient and would result in pharmaceuticallyunacceptable compositions. In addition, each excipient must of course beof sufficiently high purity to render it pharmaceutically acceptable.

Suitable pharmaceutically acceptable excipients will vary depending uponthe particular dosage form chosen. In addition, suitablepharmaceutically acceptable excipients may be chosen for a particularfunction that they may serve in the composition. For example, certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the production of uniform dosage forms. Certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the production of stable dosage forms. Certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the carrying or transporting the compound of the presentinvention once administered to the patient from one organ, or portion ofthe body, to another organ, or portion of the body. Certainpharmaceutically acceptable excipients may be chosen for their abilityto enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the followingtypes of excipients: diluents, fillers, binders, disintegrants,lubricants, glidants, granulating agents, coating agents, wettingagents, solvents, co-solvents, suspending agents, emulsifiers,sweeteners, flavoring agents, flavor masking agents, coloring agents,anticaking agents, humectants, chelating agents, plasticizers, viscosityincreasing agents, antioxidants, preservatives, stabilizers,surfactants, and buffering agents. The skilled artisan will appreciatethat certain pharmaceutically acceptable excipients may serve more thanone function and may serve alternative functions depending on how muchof the excipient is present in the formulation and what otheringredients are present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enablethem to select suitable pharmaceutically acceptable excipients inappropriate amounts for use in the invention. In addition, there areresources that are available to the skilled artisan that describepharmaceutically acceptable excipients and may be useful in selectingsuitable pharmaceutically acceptable excipients. Examples includeRemington's Pharmaceutical Sciences (Mack Publishing Company), TheHandbook of Pharmaceutical Additives (Gower Publishing Limited), and TheHandbook of Pharmaceutical Excipients (the American PharmaceuticalAssociation and the Pharmaceutical Press).

In Remington: The Science and Practice of Pharmacy, 21st edition, 2005,ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, andEncyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C.Boylan, 1988-1999, Marcel Dekker, New York, the contents of each ofwhich is incorporated by reference herein, are disclosed variouscarriers used in formulating pharmaceutically acceptable compositionsand known techniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention.

The pharmaceutical compositions of the invention are prepared usingtechniques and methods known to those skilled in the art. Some of themethods commonly used in the art are described in Remington'sPharmaceutical Sciences (Mack Publishing Company).

Therefore, another aspect of the present invention is related to amethod for preparing a pharmaceutical composition. The pharmaceuticalcomposition contains the compound disclosed herein and pharmaceuticallyacceptable excipient, carrier, adjuvant, vehicle or a combinationthereof, the method comprises mixing various ingredients. Thepharmaceutical composition containing the compound disclosed herein canbe prepared for example at normal ambient temperature and pressure.

The compound of the invention will typically be formulated into a dosageform adapted for administration to the patient by the desired route ofadministration. For example, dosage forms include those adapted for (1)oral administration such as tablets, capsules, caplets, pills, troches,powders, syrups, elixirs, suspensions, solutions, emulsions, sachets,and cachets; (2) parenteral administration such as sterile solutions,suspensions, and powders for reconstitution; (3) transdermaladministration such as transdermal patches; (4) rectal administrationsuch as suppositories; (5) inhalation such as aerosols, solutions, anddry powders; and (6) topical administration such as creams, ointments,lotions, solutions, pastes, sprays, foams, and gels.

The pharmaceutical compositions provided herein may be provided ascompressed tablets, tablet triturates, chewable lozenges, rapidlydissolving tablets, multiple compressed tablets, or enteric-coatingtablets, sugar-coated, or film-coated tablets. Enteric-coated tabletsare compressed tablets coated with substances that resist the action ofstomach acid but dissolve or disintegrate in the intestine, thusprotecting the active ingredients from the acidic environment of thestomach. Enteric-coatings include, but are not limited to, fatty acids,fats, phenylsalicylate, waxes, shellac, ammoniated shellac, andcellulose acetate phthalates. Sugar-coated tablets are compressedtablets surrounded by a sugar coating, which may be beneficial incovering up objectionable tastes or odors and in protecting the tabletsfrom oxidation. Film-coated tablets are compressed tablets that arecovered with a thin layer or film of a water-soluble material. Filmcoatings include, but are not limited to, hydroxyethylcellulose, sodiumcarboxymethylcellulose, polyethylene glycol 4000, and cellulose acetatephthalate. Film coating imparts the same general characteristics assugar coating. Multiple compressed tablets are compressed tablets madeby more than one compression cycle, including layered tablets, andpress-coated or dry-coated tablets.

The tablet dosage forms may be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination withone or more carriers or excipients described herein, including binders,disintegrants, controlled-release polymers, lubricants, diluents, and/orcolorants. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The pharmaceutical compositions provided herein may be provided as softor hard capsules, which can be made from gelatin, methylcellulose,starch, or calcium alginate. The hard gelatin capsule, also known as thedry-filled capsule (DFC), consists of two sections, one slipping overthe other, thus completely enclosing the active ingredient. The softelastic capsule (SEC) is a soft, globular shell, such as a gelatinshell, which is plasticized by the addition of glycerin, sorbitol, or asimilar polyol. The soft gelatin shells may contain a preservative toprevent the growth of microorganisms. Suitable preservatives are thoseas described herein, including methyl- and propyl-parabens, and ascorbicacid. The liquid, semisolid, and solid dosage forms provided herein maybe encapsulated in a capsule. Suitable liquid and semisolid dosage formsinclude solutions and suspensions in propylene carbonate, vegetableoils, or triglycerides. Capsules containing such solutions can beprepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and4,410,545. The capsules may also be coated as known by those of skill inthe art to modify or sustain dissolution of the active ingredient.

The pharmaceutical compositions provided herein may be provided inliquid and semisolid dosage forms, including emulsions, solutions,suspensions, elixirs, and syrups. An emulsion is a two-phase system, inwhich one liquid is dispersed in the form of small globules throughoutanother liquid, which can be oil-in-water or water-in-oil. Emulsions mayinclude a pharmaceutically acceptable non-aqueous liquids or solvent,emulsifying agent, and preservative. Suspensions may include apharmaceutically acceptable suspending agent and preservative. Aqueousalcoholic solutions may include a pharmaceutically acceptable acetal,such as a di(lower alkyl)acetal of a lower alkyl aldehyde, e.g.,acetaldehyde diethyl acetal; and a water-miscible solvent having one ormore hydroxy groups, such as propylene glycol and ethanol. Elixirs areclear, sweetened, and hydroalcoholic solutions. Syrups are concentratedaqueous solutions of a sugar, for example, sucrose, and may also containa preservative. For a liquid dosage form, for example, a solution in apolyethylene glycol may be diluted with a sufficient quantity of apharmaceutically acceptable liquid carrier, e.g., water, to be measuredconveniently for administration.

Other useful liquid and semisolid dosage forms include, but are notlimited to, those containing the active ingredient(s) provided herein,and a dialkylated mono- or poly-alkylene glycol, including,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 referto the approximate average molecular weight of the polyethylene glycol.These formulations may further comprise one or more antioxidants, suchas butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, bisulfite, sodium metabisulfite, thiodipropionic acid and itsesters, and dithiocarbamates.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax, or the like.

The pharmaceutical compositions provided herein for oral administrationmay be also provided in the forms of liposomes, micelles, microspheres,or nanosystems. Micellar dosage forms can be prepared as described inU.S. Pat. No. 6,350,458.

The pharmaceutical compositions provided herein may be provided asnon-effervescent or effervescent, granules and powders, to bereconstituted into a liquid dosage form. Pharmaceutically acceptablecarriers and excipients used in the non-effervescent granules or powdersmay include diluents, sweeteners, and wetting agents. Pharmaceuticallyacceptable carriers and excipients used in the effervescent granules orpowders may include organic acids and a source of carbon dioxide.

Coloring and flavoring agents can be used in all above dosage forms.

The compounds disclosed herein can also be coupled to soluble polymersas targeted medicament carriers. Such polymers may encompasspolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenolor polyethylene oxide polylysine, substituted by palmitoyl radicals. Thecompounds may furthermore be coupled to a class of biodegradablepolymers which are suitable for achieving controlled release of amedicament, for example polylactic acid, poly-epsilon-caprolactone,polyhydroxybutyric acid, polyorthoesters, polyacetals,polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathicblock copolymers of hydrogels.

The pharmaceutical compositions provided herein may be formulated asimmediate or modified release dosage forms, including delayed-,sustained, pulsed-, controlled, targeted-, and programmed-release forms.

The pharmaceutical compositions provided herein may be co-formulatedwith other active ingredients which do not impair the desiredtherapeutic action, or with substances that supplement the desiredaction.

The pharmaceutical compositions provided herein may be administeredparenterally by injection, infusion, or implantation, for local orsystemic administration. Parenteral administration, as used herein,include intravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular, intrasynovial, and subcutaneous administration.

The pharmaceutical compositions provided herein may be formulated in anydosage forms that are suitable for parenteral administration, includingsolutions, suspensions, emulsions, micelles, liposomes, microspheres,nanosystems, and solid forms suitable for solutions or suspensions inliquid prior to injection. Such dosage forms can be prepared accordingto conventional methods known to those skilled in the art ofpharmaceutical science (see, Remington: The Science and Practice ofPharmacy, supra).

The pharmaceutical compositions intended for parenteral administrationmay include one or more pharmaceutically acceptable carriers andexcipients, including, but not limited to, aqueous vehicles,water-miscible vehicles, non-aqueous vehicles, antimicrobial agents orpreservatives against the growth of microorganisms, stabilizers,solubility enhancers, isotonic agents, buffering agents, antioxidants,local anesthetics, suspending and dispersing agents, wetting oremulsifying agents, complexing agents, sequestering or chelating agents,cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents,and inert gases.

Suitable aqueous vehicles include, but are not limited to, water,saline, physiological saline or phosphate buffered saline (PBS), sodiumchloride injection, Ringers injection, isotonic dextrose injection,sterile water injection, dextrose and lactated Ringers injection.Non-aqueous vehicles include, but are not limited to, fixed oils ofvegetable origin, castor oil, corn oil, cottonseed oil, olive oil,peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chaintriglycerides of coconut oil, and palm seed oil. Water-miscible vehiclesinclude, but are not limited to, ethanol, 1,3-butanediol, liquidpolyethylene glycol (e.g., polyethylene glycol 300 and polyethyleneglycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone,N,N-dimethylacetamide, and dimethyl sulfoxide.

Suitable antimicrobial agents or preservatives include, but are notlimited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol,methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride(e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbicacid. Suitable isotonic agents include, but are not limited to, sodiumchloride, glycerin, and dextrose. Suitable buffering agents include, butare not limited to, phosphate and citrate. Suitable antioxidants arethose as described herein, including bisulfite and sodium metabisulfite.Suitable local anesthetics include, but are not limited to, procainehydrochloride. Suitable suspending and dispersing agents are those asdescribed herein, including sodium carboxymethylcelluose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agentsinclude those described herein, including polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan monooleate 80 and triethanolamineoleate. Suitable sequestering or chelating agents include, but are notlimited to EDTA. Suitable pH adjusting agents include, but are notlimited to, sodium hydroxide, hydrochloric acid, citric acid, and lacticacid. Suitable complexing agents include, but are not limited to,cyclodextrins, including α-cyclodextrin, β-cyclodextrin,hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, andsulfobutylether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

The pharmaceutical compositions provided herein may be formulated forsingle or multiple dosage administration. The single dosage formulationsare packaged in an ampoule, a vial, or a syringe. The multiple dosageparenteral formulations must contain an antimicrobial agent atbacteriostatic or fungistatic concentrations. All parenteralformulations must be sterile, as known and practiced in the art.

In one embodiment, the pharmaceutical compositions are provided asready-to-use sterile solutions. In another embodiment, thepharmaceutical compositions are provided as sterile dry solubleproducts, including lyophilized powders and hypodermic tablets, to bereconstituted with a sterile vehicle prior to use. In yet anotherembodiment, the pharmaceutical compositions are provided as ready-to-usesterile suspensions. In yet another embodiment, the pharmaceuticalcompositions are provided as sterile dry insoluble products to bereconstituted with a vehicle prior to use. In still another embodiment,the pharmaceutical compositions are provided as ready-to-use sterileemulsions.

The pharmaceutical compositions may be formulated as a suspension,solid, semi-solid, or thixotropic liquid, for administration as animplanted depot. In one embodiment, the pharmaceutical compositionsprovided herein are dispersed in a solid inner matrix, which issurrounded by an outer polymeric membrane that is insoluble in bodyfluids but allows the active ingredient in the pharmaceuticalcompositions diffuse through.

Suitable inner matrixes include polymethylmethacrylate,polybutyl-methacrylate, plasticized or unplasticized polyvinylchloride,plasticized nylon, plasticized polyethylene terephthalate, naturalrubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene,ethylene-vinyl acetate copolymers, silicone rubbers,polydimethylsiloxanes, silicone carbonate copolymers, hydrophilicpolymers, such as hydrogels of esters of acrylic and methacrylic acid,collagen, cross-linked polyvinyl alcohol, and cross-linked partiallyhydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinyl chloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer.

In other aspect, the pharmaceutical composition of the invention isprepared to a dosage form adapted for administration to a patient byinhalation, for example as a dry powder, an aerosol, a suspension, or asolution composition. In one embodiment, the invention is directed to adosage form adapted for administration to a patient by inhalation as adry powder. In one embodiment, the invention is directed to a dosageform adapted for administration to a patient by inhalation as a drypowder. Dry powder compositions for delivery to the lung by inhalationtypically comprise a compound disclosed herein or a pharmaceuticallyacceptable salt thereof as a finely divided powder together with one ormore pharmaceutically-acceptable excipients as finely divided powders.Pharmaceutically-acceptable excipients particularly suited for use indry powders are known to those skilled in the art and include lactose,starch, mannitol, and mono-, di-, and polysaccharides. The finelydivided powder may be prepared by, for example, micronisation andmilling. Generally, the size-reduced (e.g. micronised) compound can bedefined by a D₅₀ value of about 1 to about 10 microns (for example asmeasured using laser diffraction).

Aerosols may be formed by suspending or dissolving a compound disclosedherein or a pharmaceutically acceptable salt thereof in a liquifiedpropellant. Suitable propellants include halocarbons, hydrocarbons, andother liquefied gases. Representative propellants include:trichlorofluoromethane (propellant 11), dichlorofluoromethane(propellant 12), dichlorotetrafluoroethane (propellant 114),tetrafluoroethane (HFA-134a), 1,1-difluoroethane (HFA-152a),difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane(HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane,isobutane, and pentane. Aerosols comprising a compound of formula (A) ora pharmaceutically acceptable salt thereof will typically beadministered to a patient via a metered dose inhaler (MDI). Such devicesare known to those skilled in the art.

The aerosol may contain additional pharmaceutically-acceptableexcipients typically used with MDIs such as surfactants, lubricants,cosolvents and other excipients to improve the physical stability of theformulation, to improve valve performance, to improve solubility, or toimprove taste.

Pharmaceutical compositions adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the patient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 3(6),318 (1986).

Pharmaceutical compositions adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils. Ointments, creams andgels, may, for example, be formulated with an aqueous or oily base withthe addition of suitable thickening and/or gelling agent and/orsolvents. Such bases may thus, for example, include water and/or an oilsuch as liquid paraffin or a vegetable oil such as arachis oil or castoroil, or a solvent such as polyethylene glycol. Thickening agents andgelling agents which may be used according to the nature of the baseinclude soft paraffin, aluminum stearate, cetostearyl alcohol,polyethylene glycols, woolfat, beeswax, carboxypolymethylene andcellulose derivatives, and/or glyceryl monostearate and/or non-ionicemulsifying agents.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilizing agents,dispersing agents, suspending agents or thickening agents.

Powders for external application may be formed with the aid of anysuitable powder base, for example, talc, lactose or starch. Drops may beformulated with an aqueous or non-aqueous base also comprising one ormore dispersing agents, solubilizing agents, suspending agents orpreservatives.

Topical preparations may be administered via one or more applicationsper day to the affected area; over skin areas occlusive dressings mayadvantageously be used. Continuous or prolonged delivery may be achievedvia an adhesive reservoir system.

Compounds or pharmaceutical compositions of the invention disclosedherein can be used in the manufacture of a medicament for treating,preventing, ameliorating or mitigating a neurological and psychiatricdisorder or disease or a cancer in a subject, as well as othermedicaments for modulating (e.g., blocking) dysfunctional glutamatetransmission, and the compounds of this invention have superiorpharmacokinetic and pharmacodynamic properties, fewer toxic side-effect.

Specifically, the amount of the compound of compositions of the presentinvention can effectively and detectably modulate dysfunctionalglutamate transmission. The compounds or pharmaceutical compositions ofthe invention may be used for preventing, treating or alleviatingdiseases relating to dysfunctional glutamate transmission, wherein suchdiseases include glioma, breast cancer, melanoma; amyotrophic lateralsclerosis (ALS), chronic neuropathy pain, multiple sclerosis, ataxia,Parkinson's, Huntington's, Tourette syndrome, epilepsy, dystonia,Fragile X syndrome, disorders resulting from traumatic brain/spinal cordinjuries, disorders resulting from cerebral ischemia; depression,anxiety, bipolar disorder, schizophrenia, obsessive compulsive disorder,autism, alcohol/drug addiction; vascular and Alzheimer's dementia,glaucoma induced optical neuropathy and attention deficit/hyperactivedisorder (ADHD).

In one embodiment, the therapies disclosed herein compriseadministrating a safe and effective amount of the compound of theinvention or the pharmaceutical composition containing the compound ofthe invention to patients in need. Each example disclosed hereincomprises the method of treating the diseases above comprisingadministrating a safe and effective amount of the compound of theinvention or the pharmaceutical composition containing the compound ofthe invention to patients in need.

In one embodiment, the compound of the invention or the pharmaceuticalcomposition thereof may be administered by any suitable route ofadministration, including both systemic administration and topicaladministration. Systemic administration includes oral administration,parenteral administration, transdermal administration and rectaladministration. Parenteral administration refers to routes ofadministration other than enteral or transdermal, and is typically byinjection or infusion. Parenteral administration includes intravenous,intramuscular, and subcutaneous injection or infusion. Topicaladministration includes application to the skin as well as intraocular,intravaginal, inhaled and intranasal administration. In one embodiment,the compound of the invention or the pharmaceutical composition thereofmay be administered orally. In another embodiment, the compound of theinvention or the pharmaceutical composition thereof may be administeredby inhalation. In a further embodiment, the compound of the invention orthe pharmaceutical composition thereof may be administered intranasal.

In one embodiment, the compound of the invention or the pharmaceuticalcomposition thereof may be administered once or according to a dosingregimen wherein multiple doses are administered at varying intervals oftime for a given period of time. For example, doses may be administeredone, two, three, or four times per day. In one embodiment, a dose isadministered once per day. In a further embodiment, a dose isadministered twice per day. Doses may be administered until the desiredtherapeutic effect is achieved or indefinitely to maintain the desiredtherapeutic effect. Suitable dosing regimens for the compound of theinvention or the pharmaceutical composition thereof depend on thepharmacokinetic properties of that compound, such as its absorption,distribution, and half-lives of metabolism and elimination, which can bedetermined by the skilled artisan. In addition, suitable dosingregimens, including the duration such regimens are administered, for thecompound of the invention or the pharmaceutical composition thereofdepend on the disorder being treated, the severity of the disorder beingtreated, the age and physical condition of the patient being treated,the medical history of the patient to be treated, the nature ofconcurrent therapy, the desired therapeutic effect, and like factorswithin the knowledge and expertise of the skilled artisan. It will befurther understood by such skilled artisans that suitable dosingregimens may require adjustment given an individual patient's toleranceto the dosing regimen or over time as individual patient needs change.

The compounds of the present invention may be administered eithersimultaneously with, or before or after, one or more other therapeuticagents. The compounds of the present invention may be administeredseparately, by the same or different route of administration, ortogether in the same pharmaceutical composition as the other agents.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 1-1000 mg of active ingredients for asubject of about 50-70 kg, preferably about 1-500 mg or about 1-250 mgor about 1-150 mg or about 0.5-100 mg or about 1-50 mg of activeingredients. The therapeutically effective dosage of a compound, thepharmaceutical composition, or the combinations thereof, is dependent onthe species of the subject, the body weight, age and individualcondition, the disorder or disease or the severity thereof beingtreated. A physician, clinician or veterinarian of ordinary skill canreadily determine the effective amount of each of the active ingredientsnecessary to prevent, treat or inhibit the progress of the disorder ordisease.

The above-cited dosage properties can be correlated with in vitro and invivo tests using advantageously mammals, e.g., mice, rats, dogs,non-human primates, such as monkeys or isolated organs, tissues andpreparations thereof. The compounds of the present invention can beapplied in vitro in the form of solutions, e.g., preferably aqueoussolutions, and in vivo via topically, inhalingly, enterally orparenterally, advantageously intravenously, e.g., as a suspension or inaqueous solution.

In one embodiment, a therapeutically effective dosage of the compounddisclosed herein from about 0.1 mg to about 1,000 mg per day. Thepharmaceutical compositions should provide a dosage of from about 0.1 mgto about 1,000 mg of the compound. In a special embodiment,pharmaceutical dosage unit forms are prepared to provide from about 1 mgto about 1,000 mg, about 10 mg to about 500 mg, about 20 mg to about 200mg, about 25 mg to about 100 mg, or about 30 mg to about 60 mg of theactive ingredient or a combination of essential ingredients per dosageunit form. In a special embodiment, pharmaceutical dosage unit forms areprepared to provide about 1 mg, 5 mg, 10 mg, 20 mg, 25 mg, 50 mg, 100mg, 250 mg, 500 mg, 1000 mg of the active ingredient.

Aspects of the Invention

The invention is further defined by the following aspects:

Aspect 1. A compound having Formula (A):

wherein,

-   -   X is NH, O, S or Se;    -   W₁ or W₂ is CH or N, provided that W₁ and W₂ are not both N;    -   R₁ and R₂ are the same, or they are different, and are        independently selected from the group consisting of:        -   Hydrogen and        -   GR^(a), wherein G is absent, —C(O)— or —C(O)O— and R^(a) is            a saturated straight or branched alkyl of from one to four            carbon atoms, or a saturated cycloalkyl of from three to six            carbon atoms, provided that R₁ and R₂ are not both GR^(a),            wherein G is not absent;    -   Y_(q) is selected from the group consisting of hydrogen,        deuterium, SF₅, CF₃, OCF₃, SCF₃, S(O)CF₃, S(O)₂CF₃, CN, SCN,        S(O)CH₃, S(O)₂CH₃, NO₂, and wherein q is 1 or 2; provided that        when q is 2, Y₁ and Y₂ can be the same, or different, and they        are not both hydrogen, or both deuterium, or one each of        hydrogen and deuterium;    -   or a pharmaceutically acceptable salt thereof, and    -   with the proviso that when W₁ and W₂ are CH, the compound of        Formula (A) is not one of the following compounds:

wherein R₁ or R₂ are as above defined; and

with the proviso that when W₁ or W₂ is N, the compound of Formula (A) isnot one of the following compounds:

wherein R₁ or R₂ are as above defined.

Aspect 2. The compound of aspect 1, wherein X is NH.

Aspect 3. The compound of aspect 1, wherein X is O.

Aspect 4. The compound of aspect 1, wherein X is S.

Aspect 5. The compound of aspect 1, wherein X is Se.

Aspect 6. The compound of any one of aspects 1 to 5, wherein W₁ and W₂are CH.

Aspect 7. The compound of aspect 1, wherein W₁ or W₂ is N, provided thatW₁ and W₂ are not both N.

Aspect 8. The compound of any one of aspects 1 to 5, wherein Y₁ or Y₂ ishydrogen or deuterium, provided that Y₁ and Y₂ are not: both hydrogen,or both deuterium, or one each of hydrogen and deuterium.

Aspect 9. The compound of any one of aspects 1 to 8, wherein Y_(q) isSF₅ and q is 1 or 2.

Aspect 10. The compound of any one of aspects 1 to 8, wherein Y_(q) isCF₃ and q is 1 or 2.

Aspect 11. The compound of any one of aspects 1 to 8, wherein Y_(q) isOCF₃ and q is 1 or 2.

Aspect 12. The compound of any one of aspects 1 to 8, wherein Y^(q) isSCF₃ and q is 1 or 2.

Aspect 13. The compound of any one of aspects 1 to 8, wherein Y_(q) isS(O)CF₃ and q is 1 or 2.

Aspect 14. The compound of any one of aspects 1 to 8, wherein Y_(q) isS(O)₂CF₃ and q is 1 or 2.

Aspect 15. The compound of any one of aspects 1 to 8, wherein Y_(q) isCN and q is 1 or 2.

Aspect 16. The compound of any one of aspects 1 to 8, wherein Y_(q) isSCN and q is 1 or 2.

Aspect 17. The compound of any one of aspects 1 to 8, wherein Y_(q) isS(O)CH₃ and q is 1 or 2.

Aspect 18. The compound of any one of aspects 1 to 8, wherein Y_(q) isS(O)₂CH₃ and q is 1 or 2.

Aspect 19. The compound of any one of aspects 1 to 8, wherein Y_(q) isNO₂ and q is 1 or 2.

Aspect 20. The compound of any one of aspects 1 to 19, wherein R₁ or R₂is hydrogen.

Aspect 21. The compound of any one of aspects 1 to 19, wherein R₁ or R₂is GR^(a), wherein G is absent and R^(a) is a straight or branched alkylof from one to four carbon atoms, and is selected from the groupconsisting of: —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃,—CH₂CH(CH₃)₂, and —C(CH₃)₃.

Aspect 22. The compound of any one of aspects 1 to 19, wherein R₁ or R₂is GR^(a), wherein G is absent and R^(a) is a cycloalkyl of from threeto six carbon atoms, and is selected from the group consisting of:

optionally, R^(a) is substituted with C₁-C₄ alkyl.

Aspect 23. The compound of any one of aspects 1 to 19, wherein one of R₁and R₂ is GR^(a), wherein G is —C(O)— and R^(a) is a saturated straightor branched alkyl of from one to four carbon atoms, or a saturatedcycloalkyl of from three to six carbon atoms, and is selected from thegroup consisting of:

optionally, R^(a) is substituted with C₁-C₄ alkyl.

Aspect 24. The compound of any one of aspects 1 to 19, wherein one of R₁and R₂ is GR^(a), wherein G is —C(O)O— and R^(a) is a saturated straightor branched alkyl having from one to four carbon atoms, or a saturatedcyclic alkyl having from three to six carbon atoms, and is selected fromthe group consisting of:

optionally, R^(a) is optionally substituted with C₁-C₄ alkyl.

Aspect 25. The compound of any one of aspects 1 to 24, wherein R^(a) isselected from the group consisting of a saturated straight or branchedalkyl of from one to four carbon atoms, and a saturated cycloalkyl offrom three to six carbon atoms, wherein one or more of said carbon atomsis, optionally, an asymmetric atom.

Aspect 26. The compound of aspect 1, wherein W₁ and W₂ are CH, X is N,Y₁ is SF₅, Y₂ is H or D.

Aspect 27. The compound of aspect 1, wherein W₁ and W₂ are CH, X is N,Y₁ and Y₂ are SF₅.

Aspect 28. The compound of aspect 1, wherein W₁ and W₂ are CH, X is O,Y₁ is SF₅, Y₂ is H or D.

Aspect 29. The compound of aspect 1, wherein W₁ and W₂ are CH, X is O,Y₁ and Y₂ are SF₅.

Aspect 30. The compound of aspect 1, wherein W₁ and W₂ are CH, X is S,Y₁ is SF₅, Y₂ is H or D.

Aspect 31. The compound of aspect 1, wherein W₁ and W₂ are CH, X is S,Y₁ and Y₂ are SF₅.

Aspect 32. The compound of aspect 1, wherein W₁ and W₂ are CH, X is Se,Y₁ is SF₅, Y₂ is H or D.

Aspect 33. The compound of aspect 1, wherein W₁ and W₂ are CH, X is Se,Y₁ and Y₂ are SF₅.

Aspect 34. The compound of aspect 1, wherein W₁ and W₂ are CH, X is Se,Y₁ is selected from the group consisting of CF₃, OCF₃, SCF₃, S(O)CF₃,S(O)₂CF₃, CN, SCN, S(O)CH₃, S(O)₂CH₃, and NO₂, Y₂ is H or D.

Aspect 35. The compound of aspect 1, wherein W₁ or W₂ is N, X is N or Oor S or Se, Y₁ is SF₅, Y₂ is H or D.

Aspect 36. The compound of aspect 1, wherein W₁ or W₂ is N, X is N or Oor S or Se, Y₁ is CF₃, Y₂ is H or D.

Aspect 37. The compound of aspect 1, wherein W₁ or W₂ is N, X is N or Oor S or Se, Y₁ is OCF₃, Y₂ is H or D.

Aspect 38. The compound of aspect 1, wherein W₁ or W₂ is N, X is N or Oor S or Se, Y₁ is selected from the group consisting of SCF₃, S(O)CF₃,S(O)₂CF₃, CN, SCN, S(O)CH₃, S(O)₂CH₃, and NO₂, Y₂ is H or D.

Aspect 39. A compound selected from the group consisting of

and pharmaceutically acceptable salts thereof.

Aspect 40. A pharmaceutical composition comprising a therapeuticallyeffective amount of at least one compound according to any one ofaspects 1 to 39, or a pharmaceutically acceptable salt thereof.

Aspect 41. The pharmaceutical composition of aspect 40, furthercomprising a pharmaceutically acceptable excipient, carrier, adjuvant,solvent, support or a combination thereof.

Aspect 42. The pharmaceutical composition of aspect 40, furthercomprising therapeutically effective amounts of one or more, optional,adjunctive active ingredients.

Aspect 43. The pharmaceutical composition of aspect 42, wherein theadjunctive active ingredient is for preventing or treating aneurological and psychiatric disorder or disease, and comprises anantipsychotic, an atypical antipsychotic, an antiepileptic, ananti-Parkinson's disease drug, an anti-amyotrophic lateral sclerosisdrug, anti-pain drug, anti-multiple sclerosis drug, spinal cord injuryor a combination thereof.

Aspect 44. The pharmaceutical composition of aspect 43, wherein theactive ingredient comprises riluzole, amitriptyline, desipramine,mirtazapine, bupropion, reboxetine, fluoxetine, trazodone, sertraline,duloxetine, fluvoxamine, milnacipran, levomilnacipran, desvenlafaxine,vilazodone, venlafaxine, dapoxetine, nefazodone, femoxetine,clomipramine, citalopram, escitalopram, paroxetine, lithium carbonate,buspirone, olanzapine, quetiapine, risperidone, ziprasidone,aripiprazole, perospirone, clozapine, modafinil, mecamylamine,cabergoline, adamantane, imipramine, pramipexole, thyroxine,dextromethorphan, quinidine, naltrexone, samidorphan, buprenorphine,melatonin, alprazolam, pipamperone, vestipitant, perphenazine,midazolam, triazolam, estazolam, diazepam, flurazepam, nitrazepam,clonazepam, temazepam, flunitrazepam, oxazepam, zolpidem, zaleplon,zopiclone, eszopiclone, indiplon, tiagabine, gaboxadol, clomipramine,doxepin, chloral hydrate, haloperidol, chlorpromazine, carbamazepine,promethazine, lorazepam, hydroxyzine, aspirin, diphenhydramine,chlorpheniramine, lendormin, ramelteon, tasimelteon, agomelatine,mianserin, femoxetine, nabilone, doxepin, gabapentin, chlordiazepoxide,suvorexant, Xuezang Guben or a combination thereof.

Aspect 45. The pharmaceutical composition of aspect 42, wherein theadjunctive active ingredient is for preventing or treating a cancer, andcomprises a chemotherapeutic agent.

Aspect 46. The pharmaceutical composition of aspect 45, wherein saidadjunctive active agent, or chemotherapeutic agent is selected from thegroup consisting of: cytotoxic agent, cisplatin, doxorubicin, taxotere,taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel,docetaxel, the epothilones, tamoxifen, 5-fluorouracil, methoxtrexate,temozolomide, cyclophosphamide, SCH 66336, tipifarnib, R115777,L778,123, BMS 214662, Iressa®, Tarceva®, C225, GLEEVEC®, Intron®,Peg-Intron®, aromatase combinations, ara-C, adriamycin, ercept,gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan,Chlorambucil, Pipobroman, Triethylenemelamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin,oxaliplatin, Pentostatine, Vinblastine, Vincristine, Vindesine,Bleomycin, Dactinomycin, Daunorubicin, Epirubicin, Idarubicin,Mithramycin™, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone,Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone,Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide,Toremifene, goserelin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin,Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa,Altretamine, Melphalan, Trastuzumab, Fulvestrant, Exemestane,Ifosfomide, Rituximab, Campath, leucovorin, and dexamethasone,bicalutamide, carboplatin, chlorambucil, letrozole, megestrol, andvalrubicin.

Aspect 47. Use of the compound according to any one of aspects 1 to 40or the pharmaceutical composition according to any one of claims 40 to46 in the manufacture of a medicament for preventing, treating orlessening a disorder or disease in a patient by modulating glutamatetransmission in said patient.

Aspect 48. The use of the compound or pharmaceutical compositionaccording to aspect 47, wherein the disorder or disease is aneurological and psychiatric disorder or disease or a disorder ordisease affecting the central nervous system.

Aspect 49. The use of the compound or pharmaceutical compositionaccording to aspect 48, wherein the neurological and psychiatricdisorder or disease, or the disorder or disease affecting the CNS, isselected from the group consisting of amyotrophic lateral sclerosis,chronic neuropathy pain, multiple sclerosis, ataxia, Parkinson's,Huntington's, Tourette syndrome, epilepsy, dystonia, Fragile X syndrome,disorders resulting from traumatic brain/spinal cord injuries, disordersresulting from cerebral ischemia; depression, anxiety, bipolar disorder,schizophrenia, obsessive compulsive disorder, autism, alcohol/drugaddiction; vascular and Alzheimer's dementia, glaucoma induced opticalneuropathy and attention deficit/hyperactive disorder.

Aspect 50. The use of the compound or pharmaceutical compositionaccording to aspect 47, wherein the disorder or disease is a cancer.

Aspect 51. The use of the compound or pharmaceutical compositionaccording to aspect 50, wherein the cancer is selected from the groupconsisting of glioma, breast cancer and melanoma.

Aspect 52. The compound according to any one of aspects 1 to 39 or thepharmaceutical composition according to any one of aspects 40 to 46 foruse in preventing, treating or lessening a disorder or disease in ahuman patient by modulating glutamate transmission in said patient.

Aspect 53. The compound or pharmaceutical composition for use accordingto aspect 52, wherein the disorder or disease is a neurological andpsychiatric disorder or disease or a disorder or disease affecting thecentral nervous system.

Aspect 54. The compound or pharmaceutical composition for use accordingto aspect 53, wherein the neurological and psychiatric disorder ordisease, or the disorder or disease affecting the CNS, is selected fromthe group consisting of amyotrophic lateral sclerosis, chronicneuropathy pain, multiple sclerosis, ataxia, Parkinson's, Huntington's,Tourette syndrome, epilepsy, dystonia, Fragile X syndrome, disordersresulting from traumatic brain/spinal cord injuries, disorders resultingfrom cerebral ischemia; depression, anxiety, bipolar disorder,schizophrenia, obsessive compulsive disorder, autism, alcohol/drugaddiction; vascular and Alzheimer's dementia, glaucoma induced opticalneuropathy and attention deficit/hyperactive disorder.

Aspect 55. The compound or pharmaceutical composition for use accordingto aspect 52, wherein the disorder or disease is a cancer.

Aspect 56. The compound or pharmaceutical composition for use accordingto aspect 55, wherein the cancer is selected from the group consistingof glioma, breast cancer and melanoma.

Aspect 57. A method for preventing, treating or lessening a disorder ordisease in a patient by modulating glutamate transmission in saidpatient comprising administering to the patient a therapeuticallyeffective amount of a compound according to any one of aspects 1 to 39or a pharmaceutical composition according to any one of aspects 40 to46.

Aspect 58. The method of aspect 57, wherein the disorder or disease is aneurological and psychiatric disorder or disease or a disorder ordisease affecting the central nervous system.

Aspect 59. The method of aspect 58, wherein the neurological andpsychiatric disorder or disease, or the disorder or disease affectingthe CNS, is selected from the group consisting of amyotrophic lateralsclerosis, chronic neuropathy pain, multiple sclerosis, ataxia,Parkinson's, Huntington's, Tourette syndrome, epilepsy, dystonia,Fragile X syndrome, disorders resulting from traumatic brain/spinal cordinjuries, disorders resulting from cerebral ischemia; depression,anxiety, bipolar disorder, schizophrenia, obsessive compulsive disorder,autism, alcohol/drug addiction; vascular and Alzheimer's dementia,glaucoma induced optical neuropathy and attention deficit/hyperactivedisorder.

Aspect 60. The method of aspect 57, wherein the disorder or disease is acancer.

Aspect 61. The method of aspect 60, wherein the cancer is selected fromthe group consisting of glioma, breast cancer and melanoma.

EXAMPLES

The following examples are provided so that the invention might be morefully understood. However, it should be understood that theseembodiments merely provide a method of practicing the present invention,and the present invention is not limited to these embodiments.

Generally, the compounds disclosed herein may be prepared by methodsdescribed herein, wherein the substituents are as defined for Formula(A) above, except where further noted. The following non-limitingschemes and examples are presented to further exemplify the invention.

Professionals skilled in the art will recognize that the chemicalreactions described may be readily adapted to prepare a number of othercompounds disclosed herein, and alternative methods for preparing thecompounds disclosed herein are deemed to be within the scope disclosedherein. Those having skill in the art will recognize that the startingmaterials may be varied and additional steps employed to producecompounds encompassed by the present inventions, as demonstrated by thefollowing examples. In some cases, protection of certain reactivefunctionalities may be necessary to achieve some of the abovetransformations. In general, such need for protecting groups, as well asthe conditions necessary to attach and remove such groups, will beapparent to those skilled in the art of organic synthesis. For example,the synthesis of non-exemplified compounds according to the inventionmay be successfully performed by modifications apparent to those skilledin the art, e.g., by appropriately protecting interfering groups, byutilizing other suitable reagents known in the art other than thosedescribed, and/or by making routine modifications of reactionconditions. Alternatively, the known reaction conditions or the reactiondisclosed in the present invention will be recognized as havingapplicability for preparing other compounds disclosed herein.

In the examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius. Reagents were purchasedfrom commercial suppliers such as Aldrich Chemical Company, ArcoChemical Company and Alfa Chemical Company, and were used withoutfurther purification unless otherwise indicated.

Preparation of Compounds

Compounds of the present invention, including salts, esters, hydrates,or solvates thereof, can be prepared using any known organic synthesistechniques and can be synthesized according to any of numerous possiblesynthetic routes.

The reactions for preparing compounds of the present invention can becarried out in suitable solvents, which can be readily selected by oneskilled in the art of organic synthesis. Suitable solvents can besubstantially non-reactive with the starting materials (reactants), theintermediates, or products at the temperatures at which the reactionsare carried out, e.g., temperatures that can range from the solvent'sfreezing temperature to the solvent's boiling temperature. A givenreaction can be carried out in one solvent or a mixture of more than onesolvent. Depending on the particular reaction step, suitable solventsfor a particular reaction step can be selected by a skilled artisan.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry, or by chromatographic methods such as high performanceliquid chromatography (HPLC), liquid chromatography-mass spectroscopy(LCMS), or thin layer chromatography (TLC). Compounds can be purified bythose skilled in the art by a variety of methods, including highperformance liquid chromatography (HPLC) (“Preparative LC-MSPurification: Improved Compound Specific Method Optimization” Karl F.Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004,6(6), 874-883, which is incorporated herein by reference in itsentirety) and normal phase silica chromatography.

Compounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include but are not limitedto those methods described below. Specifically, the compounds of thepresent invention of Formula (A) can be synthesized by following thesteps outlined in the exemplary general synthetic schemes listed below,and the abbreviations for the reactants or for the chemical groups ofthe reactants included in the synthetic schemes are defined in theExamples.

General Synthetic Schemes (1-13)

The synthesis towards compounds having formula XI can be conductedaccording to the relevant procedures disclosed in references (Synlett,2012, 23, 15, 2219-2222; PCT International Publication No. WO2013/163244 A1), but is not limited to these disclosed procedures. Thus,an aniline derivative 1 is treated with KSCN in appropriate solventsystem to form Compound XI.

The synthesis towards compounds having formula XII can be conductedaccording to the relevant procedures disclosed in references (Journal ofOrganic Chemistry, 1990, 55, 17, 4979-4981; Tetrahedron Letters, 2011,52, 34, 4392-4394; and Bioorganic and Medicinal Chemistry Letters, 2014,24, 15, 3521-3525), but is not limited to these disclosed procedures.Thus, a nitrobenzene derivative 2 is oxidized to generate hydroxylcompound 3, followed by hydrogenation, the resulting amino compound 4 istreated with BrCN in appropriate solvent system to form Compound XII.

The synthesis towards compounds having formula XIII can be conductedaccording to the relevant procedures disclosed in references (EuropeanJournal of Organic Chemistry, 2012, 11, 2123-2126; Journal of MedicinalChemistry, 2014, 57, 17, 7325-7341; U.S. Application Publication No.2007/117818 A1), but is not limited to these disclosed procedures. Thus,a nitrobenzene derivative 5 is transformed to compound 6, followed byhydrogenation, the resulting diamino compound 7 is treated with BrCN inappropriate solvent system to form Compound XIII.

The synthesis towards compounds having formula XIV can be conductedaccording to the relevant procedures disclosed in references (EuropeanJournal of Medicinal Chemistry, 2015, 96, 92-97; Synthesis, 2016, 48,01, 85-96; and European Journal of Organic Chemistry, 2011, 25,4756-4759), but is not limited to these disclosed procedures. Thus, ananiline derivative 8 is brominated to furnish compound 9, which isfurther converted to amide compound 10. Compound 10 is treated withPOCl₃ to generate compound 11, followed by successive treatment of Seand NH₄OH, the resulting compound 13 is cyclized in appropriate solventsystem to form Compound XIV.

The synthesis towards compounds having formula XV can be conductedaccording to the relevant procedures disclosed in references (Journal ofMedicinal Chemistry, 2009, 52, 19, 6142-6152; U.S. ApplicationPublication No. 2009/270405 A1), but is not limited to these disclosedprocedures. Thus, an amino pyridine derivative 14 is treated with KSCNin appropriate solvent system to form Compound XV.

The synthesis towards compounds having formula XVI can be conductedaccording to the relevant procedures disclosed in references (PCTInternational Publication No. WO 2013/177024 A1; and PCT InternationalPublication No. WO 2009/147431 A1), but is not limited to thesedisclosed procedures. Thus, a pyridine derivative 15 is treated withBrCN in appropriate solvent system to form Compound XVI.

The synthesis towards compounds having formula XVII can be conductedaccording to the relevant procedures disclosed in references (ChemicalCommunications, 2014, 50, 85, 12911-12914; Journal of MedicinalChemistry, 2014, 57, 13, 5702-5713), but is not limited to thesedisclosed procedures. Thus, a diamino pyridine derivative 16 is treatedwith BrCN in appropriate solvent system to form Compound XVII.

The synthesis towards compounds having formula XVIII can be conductedaccording to the relevant procedures disclosed in references (U.S.Application Publication No. 2003/171395 A1; Synthesis, 2001, 14,2175-2179; Synthesis, 2016, 48, 01, 85-96; and European Journal ofOrganic Chemistry, 2011, 25, 4756-4759), but is not limited to thesedisclosed procedures. Thus, an amino pyridine derivative 17 isbrominated to furnish compound 18, which is further converted to amidecompound 19. Compound 19 is treated with POCl₃ to generate compound 20,followed by successive treatment of Se and NH₄OH, the resulting compound22 is cyclized in appropriate solvent system to form Compound XVIII.

The synthesis towards compounds having formula XIX can be conductedaccording to the relevant procedures disclosed in references (Journal ofHeterocyclic Chemistry, 2003, 40, 2, 261-268; Phosphorus, Sulfur andSilicon and the Related Elements, 2006, 181, 7, 1665-1673), but is notlimited to these disclosed procedures. Thus, an amino pyridinederivative 23 is treated with NH₄SCN to generate compound 24, which isfurther cyclized in appropriate solvent system to form Compound XIX.

The synthesis towards compounds having formula XX can be conductedaccording to the relevant procedures disclosed in references (U.S.Application Publication No. 2012/149718 A1; German ApplicationPublication No. DE2239311), but is not limited to these disclosedprocedures. Thus, a pyridine derivative 25 is treated with BrCN inappropriate solvent system to form Compound XX.

The synthesis towards compounds having formula XXI can be conductedaccording to the relevant procedures disclosed in references (Journal ofHeterocyclic Chemistry, 1990, 27, 6, 1821-1824; Chemical Communications,2014, 50, 85, 12911-12914), but is not limited to these disclosedprocedures. Thus, a diamino pyridine derivative 26 is treated with BrCNin appropriate solvent system to form Compound XXI

The synthesis towards compounds having formula XXII can be conductedaccording to the relevant procedures disclosed in references (OrganicLetters, 2016, 18, 5, 984-987; European Journal of Medicinal Chemistry,2015, 96, 92-97; and European Journal of Organic Chemistry, 2011, 25,4756-4759), but is not limited to these disclosed procedures. Thus, anamino pyridine derivative 27 is brominated to furnish compound 28, whichis further converted to amide compound 29. Compound 29 is treated withPOCl₃ to generate compound 30, followed by successive treatment of Seand NH₄OH, the resulting compound 32 is cyclized in appropriate solventsystem to form Compound XXII.

The synthesis towards compounds having formula A can be conductedstarting from amino compounds having formula I-XXII according to therelevant procedures disclosed in references, but is not limited to thesedisclosed procedures.

Wherein, R₁ and R₂ are not both H, Z is a leaving group that can beselected from Cl, Br, or I. The amino compounds I-XXII can be convertedto corresponding N-acyl or N-acyloxy compounds via typical N-acylationprocedures (Journal of Medicinal Chemistry, 2012, 55, 11, 5554-5565;U.S. Application Publication No. 2015/225407 A1, Bioorganic andMedicinal Chemistry, 2012, 20, 18, 5642-5648; and PCT InternationalPublication No. WO 2010/100144 A1).

Wherein, R₁ and R₂ are not both H. The amino compounds I-XXII can beconverted to corresponding N-alkyl compounds via a variety of methods(Synlett, 2013, 24, 17, 2249-2254; Chemical Communications, 2012, 48, 4,603-605; Journal of Medicinal Chemistry, 1999, 42, 15, 2828-2843;European Journal of Medicinal Chemistry, 2014, 74, 703-716; AngewandteChemie—International Edition, 2015, 54, 31, 9042-9046; and U.S.Application Publication No. 2004/44258 A1).

Preparation and Characterization of Exemplary Compounds

Compounds encompassed in the present disclosure may be prepared viadifferent schemes. Detailed preparation processes of 10 exemplarycompounds via various schemes are described below and thecharacterization results are listed as well.

Unless stated otherwise, all reagents were purchased from commercialsuppliers without further purification. Solvent drying by standardmethods was employed when necessary. The plates used for thin-layerchromatography (TLC) were E. Merck silica gel 60F254 (0.24 nm thickness)precoated on aluminum plates, and then visualized under UV light (365 nmand 254 nm) or through staining with a 5% of dodecamolybdophosphoricacid in ethanol and subsequent heating. Column chromatography wasperformed using silica gel (200-400 mesh) from commercial suppliers.¹H-NMR spectra were recorded on an Agilent 400-MR NMR spectrometer(400.00 MHz for 1H) at room temperature. Solvent signal was used asreference for ¹H-NMR (CDCl₃, 7.26 ppm; CD₃OD, 3.31 ppm; DMSO-d6, 2.50ppm; D₂O, 4.79 ppm). The following abbreviations were used to explainthe multiplicities: s=singlet, d=doublet, t=triplet, q=quartet, br.s.=broad singlet, dd=double doublet, td=triple doublet, dt=doubletriplet, dq=double quartet, m=multiplet. Other abbreviations used in theexperimental details are as follows: 6=chemical shift in parts permillion downfield from tetramethylsilane, Ar=aryl, Ac=acyl,Boc=tert-butyloxy carbonyl, Bn=Benzyl, DCM=dichloromethane,DMF=N,N′-dimethylformamide, DIPEA=diisopropylethylamine,DMAP=4-(dimethylamino)pyridine, DMSO=dimethyl sulphoxide, EA=ethylacetate, Et=ethyl, Me=methyl, Hz=hertz, HPLC=high performance liquidchromatography, J=coupling constant (in NMR), min=minute(s), h=hour(s),NMR=nuclear magnetic resonance, prep=preparative, t-Bu=tert-butyl,iPr=isopropyl, TBAF=tetrabutylammonium fluoride, tert=tertiary,TFA=trifluoroacetic acid, THF=tetrahydrofuran, TLC=thin-layerchromatography.

EXAMPLES

It should be noted that embodiments of the present invention describedin detail below are exemplary for explaining the present invention only,and not be construed as limiting the present invention. Examples withouta specific technology or condition can be implemented according totechnology or condition in the documentation of the art or according tothe product instructions. The reagents or instruments withoutmanufacturers are available through conventional purchase. Those havingskill in the art will recognize that the starting materials may bevaried and additional steps employed to produce compounds encompassed bythe present inventions, as demonstrated by the following examples.

Example 1 6-(Pentafluorosulfanyl)benzo[d]thiazol-2-amine (I)

To a stirred solution of 4-(pentafluorosulfanyl)aniline (33) (500 mg,2.28 mmol) in AcOH (10 mL) was added KSCN (265 mg, 2.73 mmol) in oneportion at 20° C. After stirring for 30 min, the reaction mixture wascooled to 0° C. and a solution of Br₂ (365 mg, 2.28 mmol) in AcOH (1 mL)was added dropwise. Then the ice-bath was removed, the reaction mixturewas stirred at 20° C. for 16 h. The mixture was poured into water (100mL), and extracted with CH₂Cl₂ (3×30 mL). The combined organic phase waswashed with water saturated NaHCO₃ solution (15 mL), saturated brinewater solution (15 mL), dried over anhydrous Na₂SO₄ and evaporated. Theresidue was purified by prep-HPLC to afford the titled compound I (378mg, 60%) as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ=8.34 (d, J=2.0Hz, 1H), 7.97 (s, 2H), 7.68 (dd, J=2.2 Hz, 9.0 Hz, 1H), 7.40 (d, J=9.2Hz, 1H); MS (ESI): [M+H⁺]=276.9.

Example 2 5-(Pentafluorosulfanyl)benzo[d]thiazol-2-amine (II)

To a stirred solution of 3-(pentafluorosulfanyl)aniline (34) (400 mg,1.83 mmol) in AcOH (8 mL) was added KSCN (355 mg, 3.65 mmol) in oneportion at 20° C. After stirring for 30 min, the reaction mixture wascooled to 0° C. and a solution of Br₂ (292 mg, 1.83 mmol) in AcOH (1 mL)was added dropwise. Then the ice-bath was removed, the reaction mixturewas stirred at 20° C. for 16 h. The mixture was poured into water (100mL), and extracted with CH₂Cl₂ (3×30 mL). The combined organic phase waswashed with saturated NaHCO₃ water solution (15 mL), saturated brinewater solution (15 mL), dried over anhydrous Na₂SO₄ and evaporated. Theresidue was purified by column chromatography (silica gel, petroleumether/EtOAc=10:1-2:1) to afford the titled compound II (135 mg, 27%) asa white solid. ¹H-NMR (400 MHz, DMSO-d6) δ=7.90 (br. s, 2H), 7.87 (s,1H), 7.73 (d, J=2.4 Hz, 1H), 7.50 (dd, J=2.0, 8.8 Hz, 1H); MS (ESI):[M+H⁺]=276.8.

Example 3 6-(Pentafluorosulfanyl)benzo[d]oxazol-2-amine (III)

Step 1: 2-Nitro-5-(pentafluorosulfanyl)phenol (36)

To a stirred solution of t-BuOK (337 mg, 3 mmol) in CH₃NH₂ (2 M in THF,5 mL) at −50° C. was added dropwise a solution of1-nitro-4-(pentafluorosulfanyl)benzene (35) (249 mg, 1 mmol) and cumenehydroperoxide (80%, 0.2 mL, 1.1 mmol) in dry THF (1 mL). The resultingbrown mixture was stirred at −50° C. for 15 min followed by the additionof solid NH₄Cl (1 g) and evaporation of CH₃NH₂. The resulting mixturewas treated with aqueous HCl (1 M) to pH 1 and extracted with CH₂Cl₂(3×20 mL). The combined organic extracts were washed with aqueous NaOH(0.5 M, 3×15 mL), the alkaline extracts were collected and acidifiedwith aqueous HCl (6 M) until pH 1, and then extracted with CH₂Cl₂ (3×20mL). The combined organic phase was dried over anhydrous MgSO₄ andevaporated. The residue was purified by column chromatography (silicagel, petroleum ether/EtOAc=20:1) to afford the titled compound 36 (238mg, 90%) as a yellow oil. ¹H-NMR (400 MHz, CDCl₃) δ=10.56 (br. s, 1H),8.23 (d, J=9.2 Hz, 1H), 7.62 (d, J=2.4 Hz, 1H), 7.40 (dd, J=2.4, 9.6 Hz,1H).

Step 2: 2-Amino-5-(pentafluorosulfanyl)phenol (37)

To a solution of 2-nitro-5-(pentafluorosulfanyl)phenol (36) (616 mg,2.32 mmol) in ethanol (5 mL) was added Pd(OH)₂ (200 mg, 10% oncharcoal). The mixture was stirred under H₂ atmosphere for 3 h. Themixture was filtered and the filtrate was concentrated to give thetitled compound 37 (448 mg, 82%) as a yellow oil. ¹H-NMR (400 MHz,CDCl₃) δ=7.21 (dd, J=2.0, 8.4 Hz, 1H), 7.12 (d, J=2.0 Hz, 1H), 6.67 (d,J=8.8 Hz, 1H), 4.88 (br. s, 1H), 4.08 (br. s, 2H).

Step 3: 6-(Pentafluorosulfanyl)benzo[d]oxazol-2-amine (III)

To a stirred solution of 2-amino-5-(pentafluorosulfanyl)phenol (37) (410mg, 1.74 mmol) in CH₃CN (10 mL) was addeddi(1H-imidazol-1-yl)methanimine (562 mg, 3.49 mmol) in one portion at20° C. The reaction mixture was stirred at 80° C. for 6 h. The solventwas evaporated and the residue was purified by column chromatography(silica gel, petroleum ether/EtOAc=10:1-2:1) to afford the titledcompound III (296 mg, 65%) as a white solid. ¹H-NMR (400 MHz, DMSO-d6)δ=7.99 (d, J=2.0 Hz, 1H), 7.96 (s, 2H), 7.64 (dd, J=2.0, 8.4 Hz, 1H),7.30 (d, J=8.8 Hz, 1H); MS (ESI): [M+H⁺]=260.7.

Example 4 5-(Pentafluorosulfanyl)benzo[d]oxazol-2-amine (IV)

Step 1: 2-Nitro-4-(pentafluorosulfanyl)phenol (39)

To a stirred solution of t-BuOK (100 mg, 3 mmol) in CH₃NH₂ (2 M in THF,2 mL) at −50° C. was added dropwise a solution of1-nitro-4-(pentafluorosulfanyl)benzene (38) (249 mg, 1 mmol) and cumenehydroperoxide (80%, 84 mg, 1.1 mmol) in dry THF (1 mL). The resultingbrown mixture was stirred at −50° C. for 15 min followed by the additionof solid NH₄Cl (1 g) and evaporation of CH₃NH₂. The resulting mixturewas treated with aqueous HCl (1 M) to pH 1 and extracted with DCM (3×20mL). The combined organic extracts were washed with aqueous NaOH (0.5 M,3×15 mL), the alkaline solutions were collected and acidified withaqueous HCl (6 M) until pH 1, and then extracted with CH₂Cl₂ (3×20 mL).The combined organic phase was dried over anhydrous MgSO₄ andevaporated. The crude product 39 was obtained as a yellow oil (265 mg,100%), which was used for the next step without further purification.¹H-NMR (400 MHz, CDCl₃) δ=10.78 (br. s, 1H), 8.57 (s, 1H), 7.96 (d,J=8.4 Hz, 1H), 7.51 (s, 1H).

Step 2: 2-Amino-4-(pentafluorosulfanyl)phenol (40)

To a solution of 2-nitro-4-(pentafluorosulfanyl)phenol (39) (150 mg,0.40 mmol) in ethanol (3 mL) was added Pd(OH)₂ (80 mg, 10% on charcoal).The mixture was stirred under H₂ atmosphere for 3 h. The mixture wasfiltered and the filtrate was concentrated to give the crude product,which was purified by prep-TLC (silica gel, petroleum ether/EtOAc=3:1)to afford the titled compound 40 (70 mg, 74%) as a yellow oil. ¹H-NMR(400 MHz, CDCl₃) δ=7.14 (d, J=2.4 Hz, 1H), 7.07 (dd, J=2.0, 8.8 Hz, 1H),6.72 (d, J=8.8 Hz, 1H), 5.40 (br. s, 1H); MS (ESI): [M+H⁺]=235.8.

Step 3: 5-(Pentafluorosulfanyl)benzo[d]oxazol-2-amine (IV)

To a stirred solution of 2-amino-4-(pentafluorosulfanyl)phenol (40) (70mg, 0.30 mmol) in CH₃CN (1 mL) was added di(1H-imidazol-1-yl)methanimine(96 mg, 0.60 mmol) in one portion at 20° C. The reaction mixture wasstirred at 80° C. for 6 h. The solvent was evaporated and the residuewas purified by column chromatography (silica gel, petroleumether/EtOAc=10:1-2:1) to afford the titled compound IV (56 mg, 72%) as awhite solid. ¹H-NMR (400 MHz, DMSO-d6) δ=7.85 (s, 2H), 7.68 (s, 1H),7.52 (s, 1H); MS (ESI): [M+H⁺]=260.8.

Example 5 6-(Pentafluorosulfanyl)benzo[d][1,3]selenazol-2-amine (V)

Step 1: 2-Bromo-4-(pentafluorosulfanyl)aniline (41)

To a stirred solution of 4-(pentafluorosulfanyl)aniline (33) (500.0 mg,2.28 mmol) in AcOH (5.0 mL) was added a solution of Br₂ (364.6 mg, 2.28mmol) in AcOH (1.0 mL) slowly at 10° C. The mixture was stirred at 10°C. for 3 h. The mixture was quenched with ice-water (60 mL), extractedwith EtOAc (2×30 mL), combined extracts dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by column chromatography (silicagel, petroleum ether/EtOAc=20:1-10:1) to afford the titled compound 41(648 mg, 96%) as a yellow solid. ¹H-NMR (400 MHz, CDCl₃) δ=7.81 (d,J=2.4 Hz, 1H), 7.49 (dd, J=2.4, 9.2 Hz, 1H), 6.71 (d, J=9.2 Hz, 1H),4.46 (s, 2H).

Step 2: N-(2-bromo-4-(pentafluorosulfanyl)phenyl)formamide (42)

To a stirred solution of 2-bromo-4-(pentafluorosulfanyl)aniline (41)(1.54 g, 5.17 mmol) in dry toluene (20 mL) was added HCOOH (4.0 mL,103.30 mmol) dropwise at 20° C. The reaction was stirred at 100° C. for16 h. After that, the reaction mixture was cooled to 30° C., dilutedwith EtOAc (60 mL), successively washed with water (30 mL) and saturatedbrine water solution (30 mL), dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by column chromatography (silicagel, petroleum ether/EtOAc=20:1-5:1) to afford the titled compound 42(1.63 g, 97%) as a yellow solid. ¹H-NMR (400 MHz, DMSO-d6) δ=10.07 (s,1H), 8.44 (s, 1H), 8.39 (d, J=8.8 Hz, 1H), 8.22 (d, J=2.4 Hz, 1H), 7.96(dd, J=2.4, 8.8 Hz, 1H).

Step 3: 2-Bromo-1-isocyano-4-(pentafluorosulfanyl)benzene (43)

To a solution of N-(2-bromo-4-(pentafluorosulfanyl)phenyl)formamide (42)(400 mg, 1.23 mmol) in dry CH₂Cl₂ (10 mL) was added Et₃N (0.5 mL, 3.68mmol) at 0° C. followed by POCl₃ (282 mg, 1.84 mmol). The reaction wasstirred under 0° C.˜20° C. for 3 h. After that, saturated aqueous Na₂CO₃solution was added slowly. After stirring for 30 min, the aqueous phasewas extracted with CH₂Cl₂ (2×20 mL). The combined organic phases driedover anhydrous Na₂SO₄ and concentrated. The residue was purified bycolumn chromatography (silica gel, petroleum ether/EtOAc=50:1-20:1) togive the titled compound 43 (236 mg, 62%) as a dark oil. ¹H-NMR (400MHz, CDCl₃) δ=8.08 (d, J=2.0 Hz, 1H), 7.78 (dd, J=2.0, 8.8 Hz, 1H), 7.56(d, J=8.8 Hz, 1H).

Step 4: 2-Bromo-1-isoselenocyanato-4-(pentafluorosulfanyl)benzene (44)

To a suspension of 2-bromo-1-isocyano-4-(pentafluorosulfanyl)benzene(43) (517 mg, 1.68 mmol) in CH₂Cl₂ (10 mL) was added Se power (398 mg,5.03 mmol), benzyltriethylammonium chloride (19.10 mg, 0.084 mmol),followed by addition of aqueous NaOH solution (50%, 0.5 mL). Thereaction was stirred at 40° C. for 3 h. After that, the reaction mixturewas diluted with CH₂Cl₂ (20 mL), washed with water (10 mL) and saturatedbrine water solution (10 mL) successively, dried over anhydrous Na₂SO₄and concentrated. The residue was purified by column chromatography(silica gel, petroleum ether/EtOAc=50:1-20:1) to afford the titledcompound 44 (308 mg, 47%) as a yellow oil. ¹H-NMR (400 MHz, CDCl₃)δ=8.00 (d, J=2.4 Hz, 1H), 7.71 (dd, J=2.4, 9.2 Hz, 1H), 7.39 (d, J=8.8Hz, 1H).

Step 5: 1-(2-Bromo-4-(pentafluorosulfanyl)phenyl)selenourea (45)

To a suspension of2-bromo-1-isoselenocyanato-4-(pentafluorosulfanyl)benzene (44) (308 mg,0.80 mmol) in CH₂Cl₂ (6 mL) was added NH₄OH (134 mg, 25% in water) at20° C. The mixture was stirred at 20° C. for 15 min. The solvents in themixture were evaporated to give the titled compound 45 (322 mg, 100%) asa white solid. ¹H-NMR (400 MHz, DMSO-d6) δ=9.88 (s, 1H), 8.64 (s, 1H),8.19 (d, J=2.0 Hz, 1H), 7.96 (br. s, 1H), 7.90 (dd, J=2.4, 8.8 Hz, 1H),7.78 (d, J=8.4 Hz, 1H).

Step 6: 6-(Pentafluorosulfanyl)benzo[d][1,3]selenazol-2-amine (V)

To a stirred solution of1-(2-bromo-4-(pentafluorosulfanyl)phenyl)selenourea (45) (322 mg, 0.80mmol) in DMSO (6 mL) was added CuI (15 mg, 0.08 mmol),1,10-phenanthroline (14 mg, 0.08 mmol) at 20° C., followed by additionof Cs₂CO₃ (130 mg, 0.40 mmol). The reaction was stirred at 80° C. undernitrogen for 30 min. After that, the reaction mixture was quenched withice-water (60 mL), extracted with EtOAc (2×30 mL). The combined organicphase was washed with saturated brine water solution (30 mL), dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by prep-HPLCto afford the titled compound V (15 mg, 6%) as a white solid. ¹H-NMR(400 MHz, DMSO-d6) δ=8.30 (d, J=2.4 Hz, 1H), 8.00 (s, 2H), 7.64 (dd,J=2.4, 8.8 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H); MS (ESI): [M+H⁺]=324.7.

Example 6 6-(Trifluoromethyl)benzo[d][1,3]selenazol-2-amine (VI)

Step 1: N-(2-iodo-4-(trifluoromethyl)phenyl)formamide (47)

To a stirred solution of 2-iodo-4-(trifluoromethyl)aniline (46) (3.0 g,10.5 mmol) in dry toluene (30 mL) was added HCOOH (4.0 mL, 114.5 mmol)dropwise at 20° C. The reaction was stirred at 100° C. for 16 h. Themixture was cooled to 30° C., diluted with EtOAc (80 mL), washed withwater (40 mL) and saturated brine water solution (40 mL) successively,dried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby column chromatography (silica gel, petroleum ether/EtOAc=20:1-10:1)to give the titled compound 47 (3.1 g, 94%) as a white solid. MS (ESI):[M+H⁺]=315.7

Step 2: 2-Iodo-1-isocyano-4-(trifluoromethyl)benzene (48)

To a solution of N-(2-iodo-4-(trifluoromethyl)phenyl)formamide (47) (2.0g, 6.35 mmol) in dry CH₂Cl₂ (30 mL) was added Et₃N (2.6 mL, 19.05 mmol)at 0° C., followed by addition of POCl₃ (1.5 g, 9.52 mmol). The reactionwas stirred at 0-20° C. for 3 h, followed by dropwise addition ofaqueous saturated Na₂CO₃ solution (10 mL). After stirring for 30 min,the aqueous phase was extracted with DCM (2×30 mL). The combined organicphase dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by column chromatography (silica gel, petroleumether/EtOAc=50:1-20:1) to give the titled compound 48 (1.32 g, 70%) as adark oil.

Step 3: 2-Iodo-1-isoselenocyanato-4-(trifluoromethyl)benzene (49)

To a suspension of 2-iodo-1-isocyano-4-(trifluoromethyl)benzene (48)(1.32 g, 4.44 mmol) in CH₂Cl₂ (30 mL) was added Se power (1.05 g, 13.33mmol), benzyltriethylammonium chloride (50.70 mg, 0.22 mmol) and aqueousNaOH solution (50%, 2.0 mL). The reaction was stirred at 40° C. for 3 h.The mixture was diluted with CH₂Cl₂ (30 mL), washed with water (20 mL)and saturated brine water solution (20 mL) successively, dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by columnchromatography (silica gel, PE/EA=50:1-20:1) to give the titled compound49 (0.90 g, 54%) as a yellow oil. ¹H-NMR (400 MHz, CDCl₃) δ=8.08 (s,1H), 7.61 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H).

Step 4: 1-(2-Iodo-4-(trifluoromethyl)phenyl)selenourea (50)

To a suspension of 2-iodo-1-isoselenocyanato-4-(trifluoromethyl)benzene(49) (300 mg, 0.80 mmol) in CH₂Cl₂ (6 mL) was added NH₄OH (134 mg, 25%in water) at 20° C. The reaction was stirred at 20° C. for 15 min. Thesolvents were evaporated to give the titled compound 50 (314 mg, 100%)as a white solid. ¹H-NMR (400 MHz, DMSO-d6) δ=9.79 (s, 1H), 8.48 (s,1H), 8.16 (s, 1H), 7.76 (s, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.4Hz, 1H).

Step 5: 6-(Trifluoromethyl)benzo[d][1,3]selenazol-2-amine (VI)

To a stirred solution of 1-(2-iodo-4-(trifluoromethyl)phenyl)selenourea(50) (600.0 mg, 1.53 mmol) in DMSO (10 mL) was added CuI (29.1 mg, 0.15mmol), 1,10-phenanthroline (27.5 mg, 0.15 mmol) and Cs₂CO₃ (248.0 mg,0.76 mmol) at 20° C. The reaction was stirred at 80° C. under nitrogenfor 30 min. The mixture was quenched with ice-water (60 mL), extractedwith EtOAc (2×30 mL). The combined organic phase was washed withsaturated brine water solution (30 mL), dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by column chromatography (silicagel, petroleum ether/EtOAc=10:1-2:1) to afford the titled compound VI(226 mg, 56%) as a light yellow solid. ¹H-NMR (400 MHz, DMSO-d6) δ=8.12(d, J=1.2 Hz, 1H), 7.94 (s, 2H), 7.48 (dd, J=1.2, 8.8 Hz, 1H), 7.40 (d,J=8.8 Hz, 1H); MS (ESI): [M+H⁺]=266.7.

Example 7 6-(Trifluoromethoxy)benzo[d][1,3]selenazol-2-amine (VII)

Step 1: N-(2-bromo-4-(trifluoromethoxy)phenyl)formamide (52)

To a stirred solution of 2-bromo-4-(trifluoromethoxy)aniline (51) (3.0g, 11.7 mmol) in dry toluene (30 mL) was added HCOOH (4.3 mL, 113.7mmol) dropwise at 20° C. The reaction was stirred at 100° C. for 16 h.The mixture was cooled to 30° C., diluted with EtOAc (60 mL), washedwith water (30 mL) and saturated brine water solution (30 mL)successively, dried over anhydrous Na₂SO₄ and concentrated. The residuewas purified by column chromatography (silica gel, petroleumether/EtOAc=20:1-5:1) to afford the titled compound 52 (3.2 g, 96%) as awhite solid. ¹H-NMR (400 MHz, DMSO-d6) δ=9.90 (s, 1H), 8.37 (s, 1H),8.14 (d, J=8.8 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H), 7.45 (d, J=8.8 Hz, 1H).

Step 2: 2-Bromo-1-isocyano-4-(trifluoromethoxy)benzene (53)

To a solution of N-(2-bromo-4-(trifluoromethoxy)phenyl)formamide (52)(2.0 g, 7.04 mmol) in dry CH₂Cl₂ (30 mL) was added Et₃N (2.1 g, 21.12mmol) at 0° C., followed by addition of POCl₃ (1.6 g, 10.56 mmol). Thereaction was stirred at 0-20° C. for 3 h, followed by dropwise additionof aqueous saturated Na₂CO₃ solution (10 mL). After stirring for 30 min,the mixture was extracted with CH₂Cl₂ (2×30 mL). The aqueous phase driedover anhydrous Na₂SO₄ and concentrated. The residue was purified bycolumn chromatography (silica gel, petroleum ether/EtOAc=50:1-20:1) toafford the titled compound 53 (1.8 g, 96%) as a dark oil. ¹H-NMR (400MHz, CDCl₃) δ=7.55 (d, J=1.6 Hz, 1H), 7.51 (d, J=9.2 Hz, 1H), 7.24 (dd,J=1.6, 9.2 Hz, 1H).

Step 3: 2-Bromo-1-isoselenocyanato-4-(trifluoromethoxy)benzene (54)

To a suspension of 2-bromo-1-isocyano-4-(trifluoromethoxy)benzene (53)(1.80 g, 6.77 mmol) in CH₂Cl₂ (36 mL) was added Se power (1.60 g, 20.30mmol), benzyltriethylammonium chloride (77.52 mg, 0.34 mmol), followedby addition of aqueous NaOH solution (50%, 5 mL). The reaction wasstirred at 40° C. for 3 h. The mixture was diluted with CH₂Cl₂ (50 mL),washed with water (30 mL) and saturated brine water solution (30 mL)successively, dried over anhydrous Na₂SO₄ and concentrated. The residuewas purified by column chromatography (silica gel, petroleumether/EtOAc=50:1-20:1) to give the titled compound 54 (0.95 g, 41%) as acolorless solid. ¹H-NMR (400 MHz, CDCl₃) δ=7.49 (d, J=2.0 Hz, 1H), 7.36(d, J=8.8 Hz, 1H), 7.18 (dd, J=1.2, 8.4 Hz, 1H).

Step 4: 1-(2-Bromo-4-(trifluoromethoxy)phenyl)selenourea (55)

To a suspension of2-bromo-1-isoselenocyanato-4-(trifluoromethoxy)benzene (54) (820 mg,2.38 mmol) in CH₂Cl₂ (10 mL) was added NH₄OH (400 mg, 25% in water) at20° C. The reaction was stirred at 20° C. for 15 min. The solvents wereevaporated to give the titled compound 55 (862 mg, 100%) as an off-whitesolid. ¹H-NMR (400 MHz, DMSO-d6) δ=9.78 (s, 1H), 8.45 (s, 1H), 7.76 (d,J=2.0 Hz, 1H), 7.74 (br. s, 1H), 7.56 (d, J=9.2 Hz, 1H), 7.42 (dd,J=1.2, 8.4 Hz, 1H).

Step 5: 6-(Trifluoromethoxy)benzo[d][1,3]selenazol-2-amine (VII)

To a stirred solution of1-(2-bromo-4-(trifluoromethoxy)phenyl)selenourea (55) (600.0 mg, 1.66mmol) in DMSO (10 mL) was added CuI (31.6 mg, 0.17 mmol),1,10-phenanthroline (30.0 mg, 0.17 mmol) at 20° C., followed by additionof Cs₂CO₃ (270.0 mg, 0.83 mmol). The reaction was stirred at 80° C.under nitrogen for 30 min. The mixture was quenched with ice-water (60mL), extracted with EA (2×30 mL). The combined organic phase was washedsaturated brine water solution (30 mL), dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by column chromatography (silicagel, petroleum ether/EtOAc=10:1-2:1) to afford the titled compound VII(106 mg, 23%) as a white solid. ¹H-NMR (400 MHz, DMSO-d6) δ=7.77 (d,J=1.2 Hz, 1H), 7.71 (s, 2H), 7.33 (d, J=8.8 Hz, 1H), 7.16 (dd, J=1.2,8.4 Hz, 1H); MS (ESI): [M+H⁺]=282.8.

Example 8 5-(Trifluoromethyl)benzo[d][1,3]selenazol-2-amine (VIII)

Step 1: N-(2-bromo-5-(trifluoromethyl)phenyl)formamide (57)

To a stirred solution of 2-bromo-5-(trifluoromethyl)aniline (56) (4.0 g,16.67 mmol) in dry toluene (40 mL) was added HCOOH (6.4 mL, 166.70 mmol)dropwise at 20° C. The reaction was stirred at 100° C. for 16 h. Themixture was cooled to 30° C., diluted with EtOAc (120 mL), washed with(30 mL) and saturated brine water solution (30 mL) successively, driedover anhydrous Na₂SO₄ and concentrated. The residue was purified bycolumn chromatography (silica gel, petroleum ether/EtOAc=20:1-10:1) toafford the titled compound 57 (4.2 g, 93%) as a white solid. ¹H-NMR (400MHz, DMSO-d6) δ=10.05 (s, 1H), 8.48 (s, 1H), 8.42 (s, 1H), 7.92 (d,J=8.4 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H); MS (ESI): [M+H⁺+CH₃CN]=310.8.

Step 2: 2-Bromo-1-isocyano-5-(trifluoromethyl)benzene (58)

To a solution of N-(2-bromo-5-(trifluoromethyl)phenyl)formamide (57)(3.0 g, 11.19 mmol) in dry CH₂Cl₂ (40 mL) was added Et₃N (4.7 mL, 33.58mmol) at 0° C., followed by addition of POCl₃ (2.6 g, 16.79 mmol). Thereaction was stirred at 0° C.˜20° C. for 3 h, followed by dropwiseaddition of aqueous saturated Na₂CO₃ solution. After stirring for 30min, the mixture was extracted with CH₂Cl₂ (2×50 mL). The combinedorganic phase dried over anhydrous Na₂SO₄ and concentrated. The residuewas purified by column chromatography (silica gel, petroleumether/EtOAc=50:1-20:1) to afford the titled compound 58 (2.02 g, 68%) asa dark oil. ¹H-NMR (400 MHz, CDCl₃) δ=7.83 (d, J=8.0 Hz, 1H), 7.71 (s,1H), 7.54 (d, J=8.4 Hz, 1H).

Step 3: 2-Bromo-1-isoselenocyanato-5-(trifluoromethyl)benzene (59)

To a suspension of 2-bromo-1-isocyano-5-(trifluoromethyl)benzene (58)(2.0 g, 8.08 mmol) in CH₂Cl₂ (40 mL) was added Se power (1.92 g, 24.24mmol), benzyltriethylammonium chloride (92 mg, 0.40 mmol), followed byaddition of aqueous NaOH solution (50%, 4.0 mL). The mixture was stirredat 40° C. for 3 h. The mixture was diluted with CH₂Cl₂ (100 mL), washedwith water (50 mL) and saturated brine water solution (50 mL)successively, dried over anhydrous Na₂SO₄ and concentrated. The residuewas purified by column chromatography (silica gel, petroleumether/EtOAc=50:1-20:1) to give the titled compound 59 (1.56 g, 54%) as ayellow oil. ¹H-NMR (400 MHz, CDCl₃) δ=7.75 (d, J=8.4 Hz, 1H), 7.56 (s,1H), 7.42 (d, J=8.4 Hz, 1H).

Step 4: 1-(2-Bromo-5-(trifluoromethyl)phenyl)selenourea (60)

To a suspension of 2-bromo-1-isoselenocyanato-5-(trifluoromethyl)benzene(59) (580 mg, 1.76 mmol) in CH₂Cl₂ (10 mL) was added NH₄OH (0.33 mL, 25%in water) at 20° C. The reaction was stirred at 20° C. for 15 min. Thesolvents were evaporated to give the titled compound 60 (593 mg, 97%) asa white solid. ¹H-NMR (400 MHz, DMSO-d6) δ=9.87 (s, 1H), 8.53 (s, 1H),7.90 (d, J=8.4 Hz, 2H), 7.86 (s, 1H), 7.55 (dd, J=1.5, 8.0 Hz, 1H); MS(ESI): [M+H⁺]=346.7.

Step 5: 5-(Trifluoromethyl)benzo[d][1,3]selenazol-2-amine (VIII)

To a stirred solution of 1-(2-bromo-5-(trifluoromethyl)phenyl)selenourea(60) (500.0 mg, 1.53 mmol) in DMSO (10 mL) was added CuI (27.5 mg, 0.14mmol), 1,10-phenanthroline (26.0 mg, 0.14 mmol) at 20° C., followed byaddition of Cs₂CO₃ (235.4 mg, 0.72 mmol). The reaction was stirred at80° C. under nitrogen for 30 min. The mixture was quenched withice-water (60 mL), extracted with EA (2×40 mL). The combined organicphase was washed with saturated brine water solution (50 mL), dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by prep-HPLC(0.5% TFA in eluents) to afford the titled compound VIII (200 mg, 52%)as a light yellow solid. ¹H-NMR (400 MHz, DMSO-d6) δ=8.39 (br. s, 2H),7.98 (d, J=8.0 Hz, 1H), 7.57 (s, 1H), 7.31 (d, J=8.0 Hz, 1H); MS (ESI):[M+H⁺]=266.7.

Example 9 6-((Trifluoromethyl)thio)benzo[d][1,3]selenazol-2-amine (IX)

Step 1: 2-Bromo-4-((trifluoromethyl)thio)aniline (62)

To a stirred solution of 4-((trifluoromethyl)thio)aniline (61) (4.0 g,20.72 mmol) in DMF (40 mL) was added N-bromosuccinimide (NBS) (3.87 g,21.74 mmol). The mixture was stirred at 30° C. for 2 h. The mixture wasquenched with ice-water (120 mL), extracted with EtOAc (2×50 mL). Thecombined organic phase was washed with water (50 mL) and saturated brinewater solution (50 mL) successively, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by column chromatography (silicagel, petroleum ether/EtOAc=20:1-10:1) to afford the titled compound 62(3.60 g, 64%) as a red oil ¹H-NMR (400 MHz, CDCl₃) δ=7.70 (d, J=1.6 Hz,1H), 7.37 (dd, J=1.6, 8.0 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 4.41 (br. s,2H); MS (ESI): [M+H⁺]=273.8.

Step 2: N-(2-bromo-4-((trifluoromethyl)thio)phenyl)formamide (63)

To a stirred solution of 2-bromo-4-((trifluoromethyl)thio)aniline (62)(3.0 g, 11.03 mmol) in dry toluene (30 mL) was added HCOOH (4.3 mL,113.70 mmol) dropwise at 20° C. The reaction was stirred at 100° C. for16 h. The mixture was cooled to 30° C., diluted with EtOAc (60 mL),washed with water (50 mL) and brine (50 mL) successively. The organicphase was dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by column chromatography (silica gel, petroleumether/EtOAc=20:1-5:1) to afford the titled compound 63 (3.1 g, 94%) as awhite solid. ¹H-NMR (400 MHz, DMSO-d6) δ=10.00 (s, 1H), 8.42 (s, 1H),8.29 (d, J=8.4 Hz, 1H), 8.03 (d, J=1.6 Hz, 1H), 7.74 (dd, J=1.2, 8.4 Hz,1H); MS (ESI): [M+H⁺+CH₃CN]=340.8.

Step 3: (3-Bromo-4-isocyanophenyl)(trifluoromethyl)sulfane (64)

To a solution of N-(2-bromo-4-((trifluoromethyl)thio)phenyl)formamide(63) (3.00 g, 10.0 mmol) in dry CH₂Cl₂ (30 mL) was added Et₃N (4.17 mL,30.0 mmol) at ice-bath, followed by addition of POCl₃ (1.40 mL, 15.0mmol). The reaction was stirred under 0° C.˜20° C. for 3 h, followed bydropwise addition of saturated aqueous Na₂CO₃ solution (10 mL). Afterstirring for 30 min, the mixture was extracted with CH₂Cl₂ (2×30 mL).The combined organic phase dried over anhydrous Na₂SO₄ and concentrated.The residue was purified by column chromatography (silica gel, petroleumether/EtOAc=50:1-20:1) to afford the titled compound 64 (2.4 g, 84%) asa dark solid. ¹H-NMR (400 MHz, CDCl₃) δ=7.97 (d, J=1.6 Hz, 1H), 7.65(dd, J=1.6, 8.0 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H).

Step 4: (3-Bromo-4-isoselenocyanatophenyl)(trifluoromethyl)sulfane (65)

To a suspension of (3-bromo-4-isocyanophenyl)(trifluoromethyl)sulfane(64) (800 mg, 2.84 mmol) in CH₂Cl₂ (8 mL) was added Se power (672 mg,8.51 mmol), benzyltriethylammonium chloride (33 mg, 0.14 mmol), followedby addition of aqueous NaOH solution (50%, 1.2 mL). The reaction wasstirred at 40° C. for 2 h. After that, the reaction mixture was dilutedwith CH₂Cl₂ (50 mL). The organic phase was washed with water (50 mL) andbrine (50 mL) successively, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by column chromatography (silicagel, petroleum ether/EtOAc=50:1-20:1) to afford the titled compound 65(0.78 g, 78%) as a brown solid. ¹H-NMR (400 MHz, CDCl₃) δ=7.90 (d, J=1.6Hz, 1H), 7.60 (dd, J=1.6, 8.0 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H).

Step 5: 1-(2-Bromo-4-((trifluoromethyl)thio)phenyl)selenourea (66)

To a solution of(3-bromo-4-isoselenocyanatophenyl)(trifluoromethyl)sulfane (65) (558 mg,1.55 mmol) in CH₂Cl₂ (6 mL) was added NH₄OH (0.3 mL, 25% in water) at20° C. The reaction was stirred at 20° C. for 30 min. The solvents wereevaporated to give the titled compound 66 (486 mg, 83%) as a yellowsolid. ¹H-NMR (400 MHz, DMSO-d6) δ=9.82 (s, 1H), 8.61 (br. s, 1H), 8.02(d, J=1.6 Hz, 1H), 7.94 (br. s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.71 (dd,J=1.6, 8.4 Hz, 1H); MS (ESI): [M+H⁺]=378.7.

Step 6: 6-(Trifluoromethoxy)benzo[d][1,3]selenazol-2-amine (IX)

To a stirred solution of1-(2-bromo-4-((trifluoromethyl)thio)phenyl)selenourea (66) (400.0 mg,1.06 mmol) in DMSO (6 mL) was added CuI (20.2 mg, 0.11 mmol) and1,10-phenanthroline (19.1 mg, 0.11 mmol) at 20° C., followed by additionof Cs₂CO₃ (172.4 mg, 0.53 mmol). The reaction was stirred at 80° C.under nitrogen for 20 min. The mixture was quenched with ice-water (60mL), extracted with EtOAc (2×30 mL). The combined organic phase waswashed with saturated brine water solution (50 mL), dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by prep-HPLC to affordthe titled compound IX (40 mg, 13%) as a white solid. ¹H-NMR (400 MHz,DMSO-d6) δ=8.21 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.48 (d, J=9.2 Hz, 1H);MS (ESI): [M+H⁺]=298.8.

Example 10 6-(Pentafluorosulfanyl)-1H-benzo[d]imidazol-2-amine (X)

Step 1: N-(4-(pentafluorosulfanyl)phenyl)acetamide (67)

To a stirred solution of 4-(pentafluorosulfanyl)aniline (33) (100 mg,0.46 mmol) in CHCl₃ (1 mL) was added Et₃N (92.3 mg, 0.92 mmol), followedby addition of Ac₂O (61.2 mg, 0.46 mmol). The reaction was stirred at20° C. for 3 h, to which H₂O (20 mL) was added. The mixture wasextracted with CH₂Cl₂ (2×10 mL). The combined organic phase dried overanhydrous Na₂SO₄ and concentrated to afford the titled crude compound 67(110 mg, 92%) as a yellow solid, which was used for the next stepwithout further purification. ¹H-NMR (400 MHz, CDCl₃) δ=7.70 (d, J=9.2Hz, 2H), 7.62 (d, J=8.8 Hz, 2H), 7.42 (br. s, 1H), 2.22 (s, 3H); MS(ESI): [M+H⁺]=261.8.

Step 2: N-(2-nitro-4-(pentafluorosulfanyl)phenyl)acetamide (68)

To a solution of N-(4-(pentafluorosulfanyl)phenyl)acetamide (67) (110mg, 0.42 mmol) in conc. H₂SO₄ (1 mL) was added HNO₃ (0.3 mL, 65%)dropwise at ice-bath. The reaction was stirred at 0-20° C. for 1 h.After that, the reaction mixture was poured into ice-water (30 mL),extracted with CH₂Cl₂ (2×15 mL). The combined organic phase dried overanhydrous Na₂SO₄ and concentrated to afford the titled crude compound 68(120 mg, 93%) as a yellow solid, which was used for the next stepwithout further purification. ¹H-NMR (400 MHz, CDCl₃) δ=10.49 (br. s,1H), 8.99 (d, J=9.6 Hz, 1H), 8.65 (d, J=2.4 Hz, 1H), 8.00 (dd, J=2.4,9.6 Hz, 1H), 2.34 (s, 3H).

Step 3: 2-Nitro-4-(pentafluorosulfanyl)aniline (69)

N-(2-nitro-4-(pentafluorosulfanyl)phenyl)acetamide (68) (120 mg, 0.39mmol) was dissolved in conc. H₂SO₄ (1 mL), and the reaction was stirredat 100° C. for 15 min. The mixture was cooled to 30° C. and poured intocrushed ice, stirred for 10 min and extracted with CH₂Cl₂ (2×15 mL). Thecombined organic phase was washed with water (20 mL) and brine (20 mL)successively, dried over anhydrous Na₂SO₄ and concentrated. The crudetitled compound 69 (100 mg, 97%) was obtained as a yellow solid, whichwas used for the next step without further purification. ¹H-NMR (400MHz, CDCl₃) δ=8.58 (d, J=2.4 Hz, 1H), 7.70 (dd, J=2.4, 9.2 Hz, 1H), 6.85(d, J=9.6 Hz, 1H), 6.40 (br. s, 2H).

Step 4: 4-(Pentafluorosulfanyl)benzene-1,2-diamine (70)

To a solution of 2-nitro-4-(pentafluorosulfanyl)aniline (69) (100 mg,0.39 mmol) in EtOH (2 mL) was added Pd/C (100 mg, 10%). The reaction wasstirred at 20° C. under H₂ atmosphere for 16 h. The reaction mixture wasfiltered, and the filtrate was concentrated to afford the crude titledcompound 70 (70 mg, 80%) as a yellow solid. MS (ESI): [M+H⁺]=234.8.

Step 5: 6-(Pentafluorosulfanyl)-1H-benzo[d]imidazol-2-amine (X)

To a stirred solution of 4-(pentafluorosulfanyl)benzene-1,2-diamine (70)(70 mg, 0.30 mmol) in H₂O (1 mL) was added BrCN (32.3 mg, 0.31 mmol).The reaction was stirred at 100° C. under nitrogen for 8 h. The reactionmixture was diluted with H₂O (20 mL), treated with NH₄OH (25%) until pH10-11, and then extracted with EtOAc (2×10 mL). The combined organicphase was washed with saturated brine water solution (20 mL), dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by prep-TLC(silica gel, CH₂Cl₂/MeOH=8:1) to afford the titled compound X (30 mg,38%) as a light-yellow solid. ¹H-NMR (400 MHz, DMSO-d6) δ=11.14 (br. s,1H), 7.55 (s, 1H), 7.37 (d, J=7.2 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 6.71(br. s, 2H); MS (ESI): [M+H⁺]=259.8.

Example 11 Pharmacological Studies

In the example, the pharmacological property is described in detail withthe compound having formula I-XXII.

A. Inhibitory Effect of Compound I-XXII on Human Voltage-Gated SodiumChannels

The potential inhibitory effect of Compound I-XXII on humanvoltage-gated sodium channels (hNav1.2/1.7) was evaluated by manualpatch-clamp system according to the procedures as described. HEK293 cellline stably transfected with SCN2A/SCN9A gene was employed in this studyand Tetrodotoxin (TTX) was used as a positive control to ensure the goodquality of the assay. The results are shown in the following Table 1,while the fitting dose-response curves for Compound I are shown in FIGS.1A and 1B.

General procedure: HEK 293 cells were stably transfected with humanNav1.2 or Nav1.7 voltage-gated sodium channels. The cells are routinelymaintained in culture medium containing in 90% DMEM, 10% FBS, 100 U/mLPenicillin-Streptomycin and 400 mg/ml of G418. Before the assay, thecells were resuspended and plated onto the coverslips at 5×105 cells/per6 cm cell culture dish for use. The voltage-gated Nav1.2 and Nav1.7channel current was recorded at room temperature (25° C.) from randomlyselected transfected cells under whole-cell patch clamp systems equippedwith EPC10 USB (HEKA) or Multiclamp 700B amplifier (Molecular Devices),while electrical data was digitalized by Digidata1440A with samplingfrequency over 10 kHz and acquired with Patchmaster or pClamp10respectively. The glass electrode with resistance ranged from 2 to 3.5MW was prepared by micropipette puller P-97 (Sutter Instrument) andfilled with internal solutions (in mM): 140 KCl, 2 MgCl₂, 10 EGTA, 10HEPES and 5 MgATP (pH adjusted to 7.35 with KOH), while cells werebathed in extracellular solutions (in mM) 132 NaCl, 4 KCl, 3 CaCl₂, 0.5MgCl₂, 11.1 glucose, and 10 HEPES (pH adjusted to 7.35 with NaOH). Afterrupture, the series membrane resistance was at least 50% compensated andcapacitance was also compensated as well. All cells were voltage-clampedto a holding potential of −80 mV unless otherwise specified. The inwardsodium currents were elicited by a 20-ms voltage pulse to 10 mV from −80mV applied every 15 s. The sodium current was initially recorded for atleast 120 seconds to assess the current stability, and only cells withrecording parameters over acceptance criteria was finally used to assessthe dose response to the local perfusion of Compound I-XXII. The blankvehicle was firstly applied to the patched cells in order to establishthe recording baseline. After at least 5 min when the elicited sodiumcurrents reaches stabilization, the test compound was perfused intorecording chamber accumulatively from low to high concentrations. Thepositive control article, Tetrodotoxin (TTX), was also used to challengesame batch of cell in order to ensure the good performance of therecording system. All experiments were performed in triplicate for IC₅₀determination. Upon data acquisition, the PatchMaster or pClamfitsoftware were used to extract the peak current from the original rawdata, while the peak current inhibition was defined by equation as shownbelow.

${{Peak}{current}{inhibition}} = {\left( {1 - \frac{{Peak}{current}_{compound}}{{Peak}{current}_{vehicle}}} \right) \times 100}$

The dose response curve for the test compound was plotted with %inhibition against the dose concentration of the test compound usingGraphpad Prism 5.0 software, and then the data was fit to a sigmoiddose-response curve with variable slope for IC₅₀ determination.

TABLE 1 Inhibitory effect of the test compound on human Nav1.2/1.7channels Test Article hNav1.2 IC₅₀ (μM) hNav1.7 IC₅₀ (μM) Compound I4.669 0.682 Compound V 4.372 0.722 Compound VI 10.144 0.745 Compound VII18.038 1.365 Compound IX 15.312 1.174

B. Compound I Testing on Mechanical Allodynia in SNL (Spinal NerveLigation) Rats

SNL model is a commonly used model to measure surgical inducedneuropathic pain. The goal of the study was to evaluate the efficacy ofCompound I to attenuate mechanical allodynia in SNL model inSprague-Dawley rats.

In this study, SNL model was created following typical procedure and theapproved drug Tapentadol (XW-TAP) was used as reference compound.Gabapentin was applied as positive control for model validation.

Experimental groups are showed in Table 2.

TABLE 2 Experimental groups. Dose Route Test Dose Volume of time GroupModel Treatment (mg/kg) (mL/kg) Admin point N 1 SNL Compound I 5 5 i.p.0.5 h 10 2 SNL Tapentadol 10 5 i.p. 0.5 h 10

Dose Formulation:

1) 5 mg/kg Compound I: Added 17.13 mg Compound I to 16.96 mL 0.5%methylcellulose in normal saline solution, vortexed to fully mix.

2) 10 mg/kg Tapentadol: Added 39.39 mg Tapentadol to 16.81 mL normalsaline solution, vortexed to fully mix.

Procedures for Mechanical Allodynia Measurement:

1) Rats were placed individually in a plastic enclosure with a meshbottom which allowed full access to the paws. Rats were acclimated for15 min prior to testing.

2) After acclimation, the mid-plantar hind paw was touched with one of aseries of eight von Frey hairs with logarithmically incrementalstiffness as follows: 3.61 (0.4 g), 3.84 (0.6 g), 4.08 (1 g), 4.31 (2g), 4.56 (4 g), 4.74 (6 g), 4.93 (8 g) and 5.18 (15 g). The von Freyhairs were presented perpendicularly to the plantar surface withsufficient force to cause slight buckling against the paw and held forapproximately 6-8 s. Stimulation was presented at intervals of 5seconds, allowing for apparent resolution of any behavioral responses toprevious stimulus. A positive response was noted if the paw was sharplywithdrawn. Flinching immediately upon removal of the hair was alsoconsidered as a positive response. Ambulation was considered as anambiguous response and in such cases, the stimulus was repeated.

3) Starting with filament 4.31 (2 g), depending on response or noresponse, investigator used a filament of decreasing or increasingforce, respectively based on Dixon up-down method. Positive responsesincluded an obvious withdrawal of the hind paw from the filament, orflinching behavior immediately following removal of the filament. Themaximum force applied was filament 5.18 (15 g).

Habituation and Pre-Dose Mechanical Allodynic Baseline Measurement:

Ten days after surgery, the rats were habituated in the testingenvironment for 15 min before allodynia measurement for three days.Pre-dose baseline was taken on day 13. Rats that didn't show allodynicresponse at this point were excluded (Rats with a paw withdrawalthreshold >5 g).

FIG. 2 shows the anti-allodynic effects of the compounds in SNL rats.(*p<0.05 vs). Vehicle group by one-way ANOVA followed by Dunnett'sMultiple Comparison Test.

Results shows that Compound I reversed SNL-induced mechanical allodyniaat the dose of 5 mg/kg at 0.5 h time point post dose.

C. Pharmacokinetic Studies

For rat pharmacokinetic studies, male Sprague-Dawley rats were housedindividually and fasted overnight before use. The animal dosingexperiments were carried out in accordance to the National Institutes ofHealth Guide to the Care and Use of Laboratory Animals and the AnimalWelfare Act. For Compound I, a single dose of 5.8 mg/kg was administeredto each rat in two groups (n=5/group) via intravenous (IV) and oral (PO)administration, respectively. The vehicle used for IV administration was10% (v/v) CremophorEL in 90% PBS. The vehicle used for PO administrationwas 0.5% (w/v) methylcellulose in normal saline solution. Blood sampleswere collected at specified time-points (pre-dose, 30 minutes, 1 hour, 2hours, 4 hours, 7 hours, 8 hours, 12 hours, 24 hours) followingadministration to individual rats within IV and PO group. Blood sampleswere clotted on ice immediately, plasma samples were then isolated bycentrifugation and stored frozen (−80° C.) until further analysis. Theconcentrations of Compound I were individually determined by LC/MS/MSassay. Various pharmacokinetic parameters were calculated using Phoenix™WinNonlin® software. To quantify the bioconversion efficiency of theCompound I in the circulation system, the bioavailability of Compound Iafter PO administration was calculated.

The results are showed in Table 3 and FIG. 3.

TABLE 3 Rat pharmacokinetic parameters of Compound I. AUC_(0-last)T_(1/2) T_(max) C_(max) (h*ng/mL) (h) (h) (ng/mL) Compound I PO 76927.11 2.30 942 at 5.8 mg/kg

Finally, it should be noted that there are other ways to practice theinvention. Accordingly, embodiments of the present invention is to bedescribed as examples, but the present invention is not limited to thecontents described, further modifications may be made within the scopeof the present invention or the equivalents added in the claims.

All publications or patents cited herein are incorporated by referencein this invention.

Reference throughout this specification to “an embodiment”, “someembodiments”, “one embodiment”, “another example”, “an example”, “aspecific examples” or “some examples” means that a particular feature,structure, material, or characteristic described in connection with theembodiment or example is included in at least one embodiment or exampleof the present disclosure. Thus, the appearances of the phrases such as“in some embodiments,” “in one embodiment”, “in an embodiment”, “inanother example, “in an example,” “in a specific example,” or “in someexamples,” in various places throughout this specification are notnecessarily referring to the same embodiment or example of the presentdisclosure. Furthermore, the particular features, structures, materials,or characteristics may be combined in any suitable manner in one or moreembodiments or examples.

Although explanatory embodiments have been shown and described, it wouldbe appreciated by those skilled in the art that the above embodimentscannot be construed to limit the present disclosure, and changes,alternatives, and modifications can be made in the embodiments withoutdeparting from spirit, principles and scope of the present disclosure.

What is claimed is:
 1. A method of suppressing, ameliorating, orrelieving a symptom of a disease or disorder selected from anxiety,Parkinson's disease, or Alzheimer's disease in a patient comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of a compound selected from:6-(pentafluoro-λ⁶-sulfanyl)benzo[d]thiazol-2-amine (I):

6-(pentafluoro-λ⁶-sulfanyl)benzo[d][1,3]selenazol-2-amine (V):

6-(trifluoromethyl)benzo[d][1,3]selenazol-2-amine (VI):

and 6-((trifluoromethyl)thio)benzo[d][1,3]selenazol-2-amine (IX):

or a pharmaceutically acceptable salt of any of the foregoing.
 2. Themethod of claim 1, wherein the compound is6-(pentafluoro-λ⁶-sulfanyl)benzo[d]thiazol-2-amine (I) or apharmaceutically acceptable salt thereof:


3. The method of claim 1, wherein the compound is6-(pentafluoro-λ⁶-sulfanyl)benzo[d][1,3]selenazol-2-amine (V) or apharmaceutically acceptable salt thereof:


4. The method of claim 1, wherein the compound is6-(trifluoromethyl)benzo[d][1,3]selenazol-2-amine (VI) or apharmaceutically acceptable salt thereof.


5. The method of claim 1, wherein the compound is6-((trifluoromethyl)thio)benzo[d][1,3]selenazol-2-amine (IX) or apharmaceutically acceptable salt thereof:


6. The method of claim 1, wherein administering comprises orallyadministering.
 7. The method of claim 1, wherein administering comprisestransdermally administering.
 8. The method of claim 1, whereinadministering comprises administering a therapeutically effective amountof a pharmaceutical composition comprising the compound or apharmaceutically acceptable salt thereof.
 9. The method of claim 8,wherein, the pharmaceutical composition is an oral pharmaceuticalformulation; and administering comprises orally administering.
 10. Themethod of claim 8, wherein, the pharmaceutical composition is atransdermal pharmaceutical formulation; and administering comprisestransdermally administering.
 11. The method of claim 1, wherein thedisease or disorder is anxiety.
 12. The method of claim 1, wherein thedisease or disorder is Parkinson's disease.
 13. The method of claim 1,wherein the disease or disorder is Alzheimer's disease.